Microarray for delivery of therapeutic agent and methods of use

ABSTRACT

Microstructure arrays and methods for using and manufacturing the arrays are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/799,304, filed Mar. 15, 2013, which is incorporated herein byreference in its entirety.

TECHNICAL FIELD

The disclosure relates generally to a method and delivery system forsustained and/or controlled, transdermal administration of a therapeuticagent or drug or vaccine using an array of microstructures, and relatedfeatures thereof.

BACKGROUND

Arrays of microneedles were proposed as a way of administering drugsthrough the skin in the 1970s, for example in expired U.S. Pat. No.3,964,482. Microneedle or microstructure arrays can facilitate thepassage of drugs through or into human skin and other biologicalmembranes in circumstances where ordinary transdermal administration isinadequate. Microstructure arrays can also be used to sample fluidsfound in the vicinity of a biological membrane such as interstitialfluid, which is then tested for the presence of biomarkers.

In recent years it has become more feasible to manufacturemicrostructure arrays in a way that makes their widespread usefinancially feasible. U.S. Pat. No. 6,451,240 discloses some methods ofmanufacturing microneedle arrays. If the arrays are sufficientlyinexpensive, for example, they may be marketed as disposable devices. Adisposable device may be preferable to a reusable one in order to avoidthe question of the integrity of the device being compromised byprevious use and to avoid the potential need of resterilizing the deviceafter each use and maintaining it in controlled storage.

Despite much initial work on fabricating microneedle arrays in siliconor metals, there are significant advantages to polymeric arrays. U.S.Pat. No. 6,451,240 discloses some methods of manufacturing polymericmicroneedle arrays. Arrays made primarily of biodegradable polymers alsohave some advantages. U.S. Pat. No. 6,945,952 and U.S. Published PatentApplications Nos. 2002/0082543 and 2005/0197308 have some discussion ofmicroneedle arrays made of biodegradable polymers. A detaileddescription of the fabrication of a microneedle array made ofpolyglycolic acid is found in Jung-Hwan Park et al., “Biodegradablepolymer microneedles: Fabrication, mechanics, and transdermal drugdelivery,” J. of Controlled Release, 104:51-66 (2005). Thesebiodegradable microstructure arrays (MSA) may consist of a biodegradabletip portion containing a dried active pharmaceutical ingredient (API)and excipients in a biocompatible and water soluble polymer matrix. Abacking portion, which connects and supports the tips, may consist of abiocompatible, non-water soluble polymer matrix. Once the MSA penetratesinto the subject's skin, the tip portion rapidly dissolves and releasedthe API very quickly, resulting in a fast T_(max).

A layered microstructure array has been described for hPTH delivery(U.S. Patent No. 2011/0276028) comprising a fast dissolving drug-in-tipdistal layer and a backing layer formed of an insoluble biodegradablepolymer. Administration of these microstructure arrays typically lead tofast dissolution of the distal layer and corresponding fast systemicabsorption of the drug.

Many drugs require sustained delivery for a prolonged period of timeincluding hours, days, weeks, etc. One approach for sustained deliveryuses microprojection arrays with detachable microprojections such as inU.S. Pat. No. 8,366,677 and U.S. Application No. (Attorney Docket No.091500-0439 filed Dec. 21, 2012), which is incorporated herein byreference.

Therefore, there is a need for a microstructure array that provides forsustained or extended delivery of a therapeutic agent. Furthermore,there is a need to modulate or modify the drug release profile from themicrostructure array in order to meet therapeutic requirements fortherapeutic agents.

The microstructure arrays are preferably retained on or at theadministration site for a period of time for a suitable or desireddelivery of the therapeutic agent. One approach for maintaining thearray at the delivery site uses a microneedle device that is applied toskin and adhered using a pressure sensitive adhesive surrounding themicroneedle array, e.g. U.S. Pat. No. 8,267,889. This approach does nothold the microneedles closely to the skin except at the perimeter of thearray where the adhesive contacts the skin and the edge of the array.U.S. Pat. No. 7,184,826 describes the use of microblades for piercingthe skin to enhance delivery. To anchor the microblades, they mayinclude a prong or barb extending from the microblades or include apartial adhesive coating. Microneedle arrays including a coatingcomprising a therapeutic agent coating have also been described, e.g.U.S. Pat. No. 8,057,842.

Thus, there is also a need in the art for microprojection arrayssuitable for extended wear that provide better adhesion of themicroprojection array and/or better contact of the microprojectionsand/or arrays.

The foregoing examples of the related art and limitations relatedtherewith are intended to be illustrative and not exclusive. Otherlimitations of the related art will become apparent to those of skill inthe art upon a reading of the specification and a study of the drawings.

BRIEF SUMMARY

The following aspects and embodiments thereof described and illustratedbelow are meant to be exemplary and illustrative, not limiting in scope.

In one aspect of the invention, an array of microstructures is providedcomprising an approximately planar base and a plurality ofmicrostructures.

In one aspect, a microstructure apparatus is provided. In an embodiment,the microstructure apparatus comprises (a) an approximately planarsubstrate having a first surface and a second surface opposed thereto;and (b) a microstructure array comprising a plurality of microstructurescontacting the first surface of the substrate and fixedly attachedthereto, the microstructures being formed of a polymer matrix comprising(i) a water insoluble, biodegradable polymer, and (ii) at least onetherapeutic agent, wherein release of the therapeutic agent from thepolymer matrix is sustained for a period of at least about 1-144 hours.In an embodiment, the water insoluble polymer is selected frompolylactide, polyglycolide, and co-polymers thereof.

In embodiments, the polymer matrix comprises about 1-50% therapeuticagent. In other embodiments, the polymer matrix comprises about 10-50%therapeutic agent. In further embodiments, the polymer matrix comprisesabout 20-50% therapeutic agent. In additional embodiments, the polymermatrix comprises about 25-50% therapeutic agent. In yet furtherembodiments, the polymer matrix comprises about 30-50% therapeuticagent. In other embodiments, the polymer matrix comprises about 45-50%therapeutic agent.

In embodiments, the polymer matrix comprises about 50-99% of the waterinsoluble, biodegradable polymer. In other embodiments, the polymermatrix comprises about 50-90% of the water insoluble, biodegradablepolymer.

In embodiments, an initial release rate of the therapeutic agent fromthe polymer matrix is between about 0.05-10%/minute. In otherembodiments, an initial release rate of the therapeutic agent from thepolymer matrix is between about 0.5-10%/minute. In further embodiments,an initial release rate of the therapeutic agent from the polymer matrixis between about 1-10%/minute. In additional embodiments, an initialrelease rate of the therapeutic agent from the polymer matrix is betweenabout 2-10%/minute.

In embodiments, release of the therapeutic agent from the polymer matrixis sustained for a period of at least about 144 hours. In otherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 72 hours. In furtherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 24 hours. In yet furtherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 12 hours. In other embodiments,release of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 6 hours. In additional embodiments,release of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 3 hours. In yet further embodiments,release of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 1 hour.

In embodiments, the microstructures are detachable from the substrate.

In embodiments, the therapeutic agent is selected from a drug, a smallmolecule, a peptide or protein, or a vaccine.

In another embodiment, the microstructure apparatus comprises (a) anapproximately planar substrate having a first surface and a secondsurface opposed thereto; and (b) a microstructure array comprising aplurality of microstructures contacting the first surface of thesubstrate and fixedly attached thereto, the microstructures being formedof a polymer matrix comprising (i) at least one low molecular weightpolymer, (ii) at least one high molecular weight polymer, and (iii) atleast one therapeutic agent; wherein an initial release rate of thetherapeutic agent from the polymer matrix is between about0.05-10%/minute; and wherein release of the therapeutic agent from thepolymer matrix is sustained for a period of at least about 1-144 hours.

In embodiments, the polymer matrix comprises at least one waterinsoluble, biodegradable polymer. In further embodiments, at least oneof the low molecular weight polymer or the high molecular weight polymeris the water insoluble, biodegradable polymer. In additionalembodiments, the water insoluble, biodegradable polymer is selected frompolylactide, polyglycolide, and co-polymers thereof.

In embodiments, the initial release rate is between about0.5-10%/minute. In further embodiments, the initial release rate isbetween about 1-10%/minute. In additional embodiments, the initialrelease rate of the therapeutic agent from the polymer matrix is lessthan about 1-10%/minute.

In embodiments, the low molecular weight polymer has a molecular weightof between about 1-10K Da. In further embodiments, the high molecularweight polymer has a molecular weight of between about 50-300K Da. Inadditional embodiments, the high molecular weight polymer has amolecular weight of between about 50-70K Da.

In embodiments, the low molecular weight polymer and high molecularweight polymers are present in a ratio of about 1:1-1:10. In furtherembodiments, the low molecular weight polymer and high molecular weightpolymers are present in a ratio of about 1:1. In other embodiments, thelow molecular weight polymer and high molecular weight polymers arepresent in a ratio of about 1:4.

In embodiments, release of the therapeutic agent from the polymer matrixis sustained for a period of at least about 144 hours. In otherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 72 hours. In furtherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 24 hours. In yet furtherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 12 hours. In other embodiments,release of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 6 hours. In additional embodiments,release of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 3 hours. In yet further embodiments,release of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 1 hour.

In embodiments, the microstructures are detachable from the substrate.

In embodiments, the therapeutic agent is selected from a drug, a smallmolecule, a peptide or protein, or a vaccine.

In another embodiment a microstructure apparatus comprises (a) anapproximately planar substrate having a first surface and a secondsurface opposed thereto; and (b) a microstructure array comprising aplurality of microstructures contacting the first surface of thesubstrate and fixedly attached thereto, the microstructures being formedof a polymer matrix comprising (i) at least one biodegradable polymer,(ii) a hydrophilic component, and (iii) at least one therapeutic agent;wherein release of the therapeutic agent from the polymer matrix issustained for a period of at least about 1-144 hours.

In an embodiment, the biodegradable polymer is a water insoluble,biodegradable polymer.

In an embodiment, release of the therapeutic agent from the polymermatrix is sustained for a period of at least about 4-24 hours. Inanother embodiment, release of the therapeutic agent from the polymermatrix is sustained for a period of at least about 4-8 hours. In furtherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 144 hours. In otherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 72 hours. In furtherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 24 hours. In yet furtherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 12 hours. In other embodiments,release of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 6 hours. In additional embodiments,release of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 3 hours. In yet further embodiments,release of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 1 hour.

In an embodiment, the polymer matrix comprises about 5%-40% of thehydrophilic component. In another embodiment, the polymer matrixcomprises about 5%-10% of the hydrophilic component. In a furtherembodiment, the polymer matrix comprises about 5%-40% of the hydrophiliccomponent. In yet another embodiment, the polymer matrix comprises up toabout 40% of the hydrophilic component. In other embodiments, thepolymer matrix comprises up to about 20% of the hydrophilic component.In further embodiments, the polymer matrix comprises up to about 10% ofthe hydrophilic component.

In embodiments, an initial release rate of the therapeutic agent fromthe polymer matrix is between about 0.05-10%/minute. In otherembodiments, an initial release rate of the therapeutic agent from thepolymer matrix is between about 0.5-10%/minute. In further embodiments,an initial release rate of the therapeutic agent from the polymer matrixis between about 1-10%/minute. In yet other embodiments, an initialrelease rate of the therapeutic agent from the polymer matrix is betweenabout 2-10%/minute.

In embodiments the hydrophilic component is PEG-PLGA. In furtherembodiments, the hydrophobic polymer is selected from PLA, α-hydroxyacids, polycaprolactones, polyanhydrides, and co-polymers thereof. Inadditional embodiments, the α-hydroxy acid is PLGA.

In embodiments the microstructures are detachable from the substrate.

In embodiments, the therapeutic agent is selected from a drug, a smallmolecule, a peptide or protein, or a vaccine.

In an embodiment, the microstructure apparatus, comprises (a) anapproximately planar substrate having a first surface and a secondsurface opposed thereto; (b) a microstructure array comprising aplurality of microstructures contacting the first surface of thesubstrate and fixedly attached thereto, the microstructures being formedof a polymer matrix comprising at least one polymer and at least onetherapeutic agent; wherein a ratio of therapeutic agent to polymer inthe matrix is low; wherein an initial release rate of the therapeuticagent from the polymer matrix is between about 0.05-10%/minute; whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 1-144 hours.

In embodiments, the ratio of therapeutic agent to polymer is betweenabout 1:2 to 1:25. In further embodiments, the ratio of therapeuticagent to polymer is between about 1:2 to 1:20. In other embodiments, theratio of therapeutic agent to polymer is between about 1:2 to 1:15. Inyet further embodiments, the ratio of therapeutic agent to polymer isbetween about 1:2 to 1:10. In additional embodiments, the ratio oftherapeutic agent to polymer is between about 1:2 to 1:4.

In an embodiment, the polymer matrix comprises at least one waterinsoluble, biodegradable polymer. In further embodiments, the waterinsoluble, biodegradable polymer is selected from polylactide,polyglycolide, and co-polymers thereof.

In an embodiment, the initial release rate is between about 0.5%/minute.In further embodiments, the initial release rate of the therapeuticagent from the polymer matrix is less than 10%/minute. In additionalembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 144 hours. In otherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 72 hours. In furtherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 24 hours. In yet furtherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 12 hours. In other embodiments,release of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 6 hours. In additional embodiments,release of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 3 hours. In yet further embodiments,release of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 1 hour.

In embodiments the microstructures are detachable from the substrate.

In embodiments, the therapeutic agent is selected from a drug, a smallmolecule, a peptide or protein, or a vaccine.

In an embodiment a microstructure apparatus, comprises (a) anapproximately planar substrate having a first surface and a secondsurface opposed thereto; and (b) a microstructure array comprising aplurality of microstructures contacting the first surface of thesubstrate and fixedly attached thereto; wherein at least a portion ofthe microstructures has a distal portion dimensioned to penetrate astratum corneum layer of a subject's skin, and a proximal portion thatis dimensioned so that it does not penetrate the skin; wherein thedistal portion and proximal portion are each formed of a polymer matrixcomprising (i) a biodegradable polymer, and (ii) at least onetherapeutic agent.

In an embodiment, the apparatus further comprises a backing layerpositioned between the proximal portion and the substrate, the backinglayer being formed of a polymer matrix comprising (i) a biodegradablepolymer, and (ii) the at least one therapeutic agent. In otherembodiments, the biodegradable polymer is a water soluble biodegradablepolymer. In further embodiments, the biodegradable polymer is a waterinsoluble biodegradable polymer.

In an embodiment, the therapeutic agent is selected from a drug, a smallmolecule, a peptide or protein, or a vaccine.

In embodiments, release of the therapeutic agent from the polymer matrixis sustained for a period of at least about 0.1-24 hours. In otherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 0.5-10 hours. In furtherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 0.5-4 hours. In additionalembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 0.5-4 hours. In yet otherembodiments, release of the therapeutic agent from the polymer matrix issustained for a period of at least about 0.1-1 hours. In otherembodiments, the microstructure array is suitable to be worn for atleast 1-24 hours.

In another aspect, a method of making a sustained release microstructureapparatus, comprises

dissolving or suspending a therapeutic agent in a solvent to form atherapeutic agent solution or suspension;

dissolving at least one water insoluble, biodegradable polymer in asolvent to form a polymer solution;

mixing the therapeutic agent solution or suspension and the polymersolution or suspension to form a polymer matrix solution or suspension;

dispensing the polymer matrix solution or suspension on a mold having anarray of microstructure cavities;

filling the microstructure cavities in the mold;

removing excess solution or suspension polymer matrix on the moldsurface; and drying the matrix to form a plurality of microstructures;

dispensing a basement or backing layer on the mold surface;

drying the basement or backing layer.

In an embodiment, the method further comprises affixing the basement orbacking layer to a substrate. In another embodiment, the method furthercomprises using a nonwoven or porous film double coated with adhesive toaffix the basement or backing layer to a substrate. In a furtherembodiment, at least one of the solvents is selected from DMSO andacetonitrile. In other embodiments, filling the therapeutic agent iscrystalline, and the method further comprises heating the plurality ofmicrostructures to about 110° C. for about 1 hour; and

storing the microstructures in a dry cabinet for about 10 days. Inembodiments, the heating is performed in a convection oven.

In a further aspect, a method of modulating an initial release rate of atherapeutic agent from a microstructure apparatus comprising a pluralityof microstructures formed of a polymer matrix comprising at least onepolymer and at least one therapeutic agent, comprises:

(a) wherein the at least one polymer comprises at least one highmolecular weight polymer and at least one low molecular weight polymer,adjusting a ratio of the high molecular weight polymers to low molecularweight polymers in the polymer matrix to achieve a desired initialrelease rate of therapeutic agent from the polymer matrix;

(b) adjusting a ratio of therapeutic agent to polymer in the polymermatrix;

(c) adding at least one hydrophilic component to the polymer matrix;and/or

(d) selecting a solvent for preparing the polymer matrix that provides adesired initial release rate.

In an embodiment, (a) comprises increasing the ratio of high molecularweight polymer in the matrix to increase the initial release rate. Inanother embodiment, (a) comprises increasing the ratio of low molecularweight polymer in the matrix to decrease the initial release rate. Infurther embodiments, (b) comprises increasing the ratio of therapeuticagent in the matrix to increase the initial release rate. In additionalembodiments, (b) comprises decreasing the ratio of low molecular weightpolymer in the matrix to decrease the initial release rate.

In embodiments, (c) comprises adding the hydrophilic component as about10-40% of the matrix to increase the initial release rate.

In embodiments, the hydrophilic component is PEG-PLGA.

In embodiments, the at least one polymer is a water insoluble,biodegradable polymer. In other embodiments, the water insoluble,biodegradable polymer is selected from polylactide, polyglycolide, andco-polymers thereof.

In embodiments, (d) comprises choosing one of DMSO or acetonitrile asthe solvent. In other embodiments, (d) comprises choosing DMSO as thesolvent to lower the initial release rate. In additional embodiments,(d) comprises choosing acetonitrile as the solvent to increase theinitial release rate.

In another aspect, a microstructure apparatus, comprises a substratehaving a first surface and a second surface opposed thereto; a pluralityof microstructures extending outwardly from the first surface of thesubstrate; at least a portion of the microstructures comprising at leastone therapeutic agent; and an adhesive coating applied to at least oneof a) at least a portion of at least some of the plurality ofmicrostructures, or b) at least a portion of the substrate first surfacebetween the microstructures.

In embodiments, at least a portion of the microstructures comprise abiodegradable distal layer and at least one non-biodegradable proximallayer positioned between the distal layer and the first surface of thesubstrate.

In embodiments, at least a portion of the microstructures arebiodegradable.

In embodiments, the therapeutic agent is a drug, a small-molecule agent,a protein or peptide, or a vaccine.

In embodiments, the adhesive coating comprises an adhesive selected froma medical adhesive, a tissue adhesive, or a surgical adhesive. In otherembodiments, the medical adhesive is selected from acrylic adhesives,silicone based adhesives, hydrogel adhesives, and synthetic elastomeradhesives. In further embodiments, the tissue adhesive is acyanoacrylate polymer. In yet further embodiments, the cyanoacrylatepolymer is selected from n-butyl-2-cyanoacrylate, and isobutylcyanoacrylate. In other embodiments, the adhesive coating comprises afibrin adhesive. In yet other embodiments, the adhesive coatingcomprises a bioactive film. In additional embodiments, the adhesivecoating comprises a pressure sensitive adhesive. In further embodiments,the pressure sensitive adhesive is an acrylic pressure sensitiveadhesive. In yet further embodiments, the adhesive coating comprises arubber-based adhesive.

In embodiments, the adhesive coating is biodegradable. In otherembodiments, the adhesive coating is non-continuous. In furtherembodiments, the adhesive coating includes a plurality of holes. Inadditional embodiments, the adhesive coating is porous.

In embodiments, the adhesive coating has a reduced adhesion over time.

In embodiments, the adhesive coating is applied to at least about10-100% of the microstructures in the array. In other embodiments, atleast about 10-95% of each coated microstructure has an adhesivecoating. In further embodiments, the adhesive coating is applied to adistal portion of the microstructures. In additional embodiments, theadhesive coating is applied to a proximal portion of themicrostructures.

In an embodiment, a microstructure apparatus, comprises a substratehaving a first surface and a second surface opposed thereto; a pluralityof microstructures extending outwardly from the first surface of thesubstrate; a plurality of openings extending through the substrate andpositioned between at least some of the plurality of microstructures;and an adhesive coating applied to at least a portion of the substratesecond surface such that the adhesive is capable of contacting asubject's skin through the openings when placed on the skin.

In an embodiment, the adhesive coating is applied to all orsubstantially all of the substrate second surface. In other embodiments,the adhesive coating is applied the substrate second surface in theregion of the openings.

In an embodiment, a backing layer positioned over the adhesive coating.

In an embodiment, at least a portion of the microstructures are at leastpartially biodegradable.

In an embodiment, the therapeutic agent is a drug, a small-moleculeagent, a protein or peptide, or a vaccine.

In embodiments, the adhesive coating comprises an adhesive selected froma medical adhesive, a tissue adhesive, or a surgical adhesive. In otherembodiments, the medical adhesive is selected from acrylic adhesives,silicone based adhesives, hydrogel adhesives, and synthetic elastomeradhesives. In further embodiments, the tissue adhesive is acyanoacrylate polymer. In yet further embodiments, the cyanoacrylatepolymer is selected from n-butyl-2-cyanoacrylate, and isobutylcyanoacrylate. In other embodiments, the adhesive coating comprises afibrin adhesive. In yet other embodiments, the adhesive coatingcomprises a bioactive film. In additional embodiments, the adhesivecoating comprises a pressure sensitive adhesive. In further embodiments,the pressure sensitive adhesive is an acrylic pressure sensitiveadhesive. In yet further embodiments, the adhesive coating comprises arubber-based adhesive.

In embodiments, the adhesive coating is biodegradable. In otherembodiments, the adhesive coating is non-continuous. In furtherembodiments, the adhesive coating includes a plurality of holes. Inadditional embodiments, the adhesive coating is porous.

In embodiments, the adhesive coating has a reduced adhesion over time.

In embodiments, the adhesive coating is applied to at least about10-100% of the microstructures in the array. In other embodiments, atleast about 10-95% of each coated microstructure has an adhesivecoating. In further embodiments, the adhesive coating is applied to adistal portion of the microstructures. In additional embodiments, theadhesive coating is applied to a proximal portion of themicrostructures.

In another aspect, a system comprises the microstructure apparatus ofany one of the combined or separate above embodiments and an applicatorfor applying the microstructure apparatus to a patient's skin.

In another aspect, a method of delivering a therapeutic agent to asubject for an extended period of time, comprises applying amicrostructure apparatus of any previous claim to a skin site of thesubject; adhering the microstructure apparatus to the skin; deliveringthe therapeutic agent from the microstructure array to the subject; andremoving the microstructure apparatus after at least about 10 minutes.

In an embodiment, the microstructure apparatus is removed after at leastabout 15 minutes. In another embodiment, the microstructure apparatus isremoved after at least about 20 minutes. In a further embodiment, themicrostructure apparatus is removed after at least about 30 minutes. Inother embodiments, the microstructure apparatus is removed after atleast about 45 minutes. In yet other embodiments, the microstructureapparatus is removed after at least about 1 hour. In furtherembodiments, the microstructure apparatus is removed after at leastabout 1-24 hours. In yet further embodiments, the microstructureapparatus is removed after at least about 1-5 days.

In an embodiment, at least about 10-100% of a total dose of thetherapeutic agent is delivered to the subject. In other embodiments, atleast about 50-100% of a total dose of the therapeutic agent isdelivered to the subject. In further embodiments, at least about 60-100%of a total dose of the therapeutic agent is delivered to the subject. Inadditional embodiments, at least about 70-100% of a total dose of thetherapeutic agent is delivered to the subject. In other embodiments, atleast about 75-100% of a total dose of the therapeutic agent isdelivered to the subject. In yet other embodiments, at least about80-100% of a total dose of the therapeutic agent is delivered to thesubject. In further embodiments, at least about 90-100% of a total doseof the therapeutic agent is delivered to the subject. In additionalembodiments, at least about 95-100% of a total dose of the therapeuticagent is delivered to the subject.

In an embodiment, the method further comprises:

prior to applying the microstructure apparatus, positioning themicrostructure apparatus on a plunger of an applicator;

actuating the applicator to release the plunger;

impacting the skin with the microstructure apparatus;

removing the applicator with the microstructure apparatus remaining onthe skin site for an extended period of time.

In an embodiment, the method further comprises pressing themicrostructure apparatus against the skin site to push the adhesivethrough the openings and into contact with the skin site.

Additional embodiments of the present microstructures, arrays, methods,and the like, will be apparent from the following description, drawings,examples, and claims. As can be appreciated from the foregoing andfollowing description, each and every feature described herein, and eachand every combination of two or more of such features, is includedwithin the scope of the present disclosure provided that the featuresincluded in such a combination are not mutually inconsistent. Inaddition, any feature or combination of features may be specificallyexcluded from any embodiment of the present invention. Additionalaspects and advantages of the present invention are set forth in thefollowing description and claims, particularly when considered inconjunction with the accompanying examples and drawings.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1A-1B are microscopic images of one exemplary sustained releasemicrostructure array with 35% Clonidine in a PLGA polymer matrix. Theimage in FIG. 1A is taken from the sharp side of the microstructures.The image in FIG. 1B is taken from the wide side of the microstructures.

FIG. 2 is a microscopic image of a residual basement layer formed of aUV curable adhesive after ACN extraction. The image is taken from thesharp side of the microstructures.

FIG. 3 is a microscopic image of an exemplary sustained releasemicrostructure array after exposure to a phosphate buffer at 37° C. forone week.

FIG. 4 is a graph of % Clonidine released from microstructures formedwith 10% or 25% PLGA polymer matrices over time in minutes. The polymermatrix comprised 15%, 20%, 30%, or 44% drug load.

FIG. 5 is a graph of % drug released from microstructures formed usingDMSO or ACN as the solvent over time in minutes. The polymer matrixcomprised Clonidine or Tamsulosin at 30% or 44% drug load.

FIGS. 6A-6C are microscopic images of Clonidine in a PLGA film (drugload of 35%). FIG. 6A shows crystallization of Clonidine. FIG. 6B showsthe film after heat treatment at 110° C. for one hour and storage in adry cabinet for 10 days. FIG. 6C shows a microscope glass control.

FIG. 7 is a graph of drug release rate in μg/hr/cm² for exemplarymicrostructure arrays prepared with a LMWP to HMWP ratio of 1:1 or aLMWP to HMWP ratio of 4:1 over time in hours.

FIG. 8 is a graph of drug release rate in μg/hr/cm² for exemplarymicrostructure arrays prepared with a high drug to polymer ratio or alow drug to polymer ratio over time in hours.

FIG. 9 is a graph of drug release rate in μg/hr/cm² for exemplarymicrostructure arrays prepared with a 0%, 10%, 20%, or 40% of ahydrophilic component over time in hours.

FIGS. 10A-10B are illustrations of exemplary shapes for microstructuresincluding a funnel shape. FIG. 10A depicts a microstructure having apyramidal tip with a funnel shaped distal portion. FIG. 10B depicts amicrostructure having a conical tip, a cylindrical shank and a conicalfunnel distal portion.

FIGS. 11A-11C are illustrations of exemplary microstructure arraysshowing drug loaded in the penetrating portion of the microstructures(FIG. 11A), drug loaded in the whole or entire microstructure (FIG.11B), and drug loaded in the whole microstructure and a portion of thebacking layer or substrate (FIG. 11C).

FIGS. 12A-12C are illustrations of exemplary microstructure arrays inuse. FIG. 12B shows use of an exemplary microstructure array having drugloaded in the entire microstructure. FIG. 12A shows use of an exemplarymicrostructure array having drug loaded only in the penetrating portionof the microstructures. FIG. 12C shows use of an exemplarymicrostructure having drug loaded in the whole microstructure and aportion of the backing layer or substrate.

FIG. 13 is an illustration of an exemplary method of formingmicrostructure arrays having drug loaded in the whole microstructure anda portion of the backing layer or substrate.

FIG. 14 is an illustration of a microstructure with a full adhesivelayer.

FIG. 15 is an illustration of a microstructure with a partial adhesivecoating in one embodiment.

FIG. 16 is an illustration of a partial microstructure array with apartial adhesive coating.

FIGS. 17A-17B are illustrations of embodiments of microstructure arraygeometry.

FIGS. 18A-18B are side view illustrations of embodiments ofmicrostructure array geometry.

FIG. 19 is an illustration of a top perspective view of an exemplaryapplicator device.

It will be appreciated that the thicknesses and shapes for the variousmicrostructures have been exaggerated in the drawings to facilitateunderstanding of the device. The drawings are not necessarily “toscale.”

DETAILED DESCRIPTION

Various aspects now will be described more fully hereinafter. Suchaspects may, however, be embodied in many different forms and should notbe construed as limited to the embodiments set forth herein; rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey its scope to those skilled in theart.

The practice of the present disclosure will employ, unless otherwiseindicated, conventional methods of chemistry, biochemistry, andpharmacology, within the skill of the art. Such techniques are explainedfully in the literature. See, e.g.; A. L. Lehninger, Biochemistry (WorthPublishers, Inc., current addition); Morrison and Boyd, OrganicChemistry (Allyn and Bacon, Inc., current addition); J. March, AdvancedOrganic Chemistry (McGraw Hill, current addition); Remington: TheScience and Practice of Pharmacy, A. Gennaro, Ed., 20^(th) Ed.; Goodman& Gilman The Pharmacological Basis of Therapeutics, J. Griffith Hardman,L. L. Limbird, A. Gilman, 10^(th) Ed.

Where a range of values is provided, it is intended that eachintervening value between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the disclosure. For example, if a range of 1 μm to 8μm is stated, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μmm and 7 μmare also explicitly disclosed, as well as the range of values greaterthan or equal to 1 μm and the range of values less than or equal to 8μm.

I. DEFINITIONS

As used in this specification, the singular forms “a,” “an,” and “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, reference to a “polymer” includes a single polymer aswell as two or more of the same or different polymers; reference to an“excipient” includes a single excipient as well as two or more of thesame or different excipients, and the like.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions describedbelow.

“Biodegradable” refers to natural or synthetic materials that degradeenzymatically, non-enzymatically or both to produce biocompatible and/ortoxicologically safe by-products which may be eliminated by normalmetabolic pathways.

“Hydrophobic polymer” as used herein refers to polymers that areinsoluble or poorly soluble in aqueous solvents. “Hydrophilic polymer”as used herein refers to polymers that are soluble or substantiallysoluble in aqueous solvents.

The terms “microprotrusion”, “microprojection”, “microstructure” or“microneedle” are used interchangeably herein to refer to elementsadapted to penetrate or pierce at least a portion of the stratum corneumor other biological membranes. For example, illustrative microstructuresmay include, in addition to those provided herein, microblades asdescribed in U.S. Pat. No. 6,219,574, edged microneedles as described inU.S. Pat. No. 6,652,478, and microprotrusions as described in U.S.Patent Publication No. U.S. 2008/0269685.

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.

“Substantially” or “essentially” means nearly totally or completely, forinstance, 90-95% or greater of some given quantity.

“Transdermal” refers to the delivery of an agent into and/or through theskin for local and/or systemic therapy. The same inventive principlesapply to administration through other biological membranes such as thosewhich line the interior of the mouth, gastro-intestinal tract,blood-brain barrier, or other body tissues or organs or biologicalmembranes which are exposed or accessible during surgery or duringprocedures such as laparoscopy or endoscopy.

A material that is “water-soluble” may be defined as soluble orsubstantially soluble in aqueous solvents, such that the materialdissolves into, within or below the skin or other membrane which issubstantially aqueous in nature.

II. MICROSTRUCTURE ARRAYS A. Microstructure Array Composition

General features of microstructure arrays suitable for use in theinstant arrays and methods are described in detail in U.S. PatentPublication No. 2008/0269685, U.S. Patent Publication No. 2011/0006458,and U.S. Patent Publication No. 2011/0276028, the entire contents ofwhich are explicitly incorporated herein by reference.

In one aspect, the microstructure array is a sustained release arraythat provides sustained release of at least one therapeutic agent fromthe microstructures. The array typically includes an approximatelyplanar substrate, base or backing having a first surface and a secondsurface opposed thereto. At least one, but preferably a plurality ofmicrostructures contact the first surface and are fixedly attachedthereto. The microstructures typically project from the substrate at anangle. The microstructures may be attached to the substrate by anysuitable means known in the art. In one, non-limiting embodiment, themicrostructures are attached to the substrate using an adhesive.Suitable adhesives include, but are not limited to, acrylic adhesives,acrylate adhesives, pressure sensitive adhesives, double-sided adhesivetape, double sided adhesive coated nonwoven or porous film, and UVcurable adhesives. One exemplary double-sided tape is the #1513double-coated medical tape available from 3M. One exemplary, butnon-limiting, UV curable adhesive is the 1187-M UV light-curableadhesive available from Dymax. It will be appreciated that any medicaldevice adhesive known in the art would be suitable. The substrate, baseor backing may be rigid, semi-rigid or flexible as needed based on theuse of the microstructure array.

In another embodiment, the microstructure arrays include a proximal,backing or basement layer. In further embodiments, the microstructurearrays include a proximal backing or basement layer positioned betweenthe microstructures and the substrate. It will be appreciated that thebacking layer may also function as the substrate, base or backing suchthat the backing layer extends between the microstructures. Inembodiments, the proximal or backing layer or portion may be designednot to penetrate the skin.

The substrate and/or backing layer are typically formed of one or morebiocompatible and/or non-biodegradable materials. The substrate and/orbacking layer may be formed of any suitable material that provides thenecessary support for the microstructures. Preferably, the substrateand/or backing layer is formed of a synthetic or natural material thatis biocompatible at least on the surface that may contact the patient'sskin. Suitable materials include, but are not limited to, metals,silicon and/or polymers. In an embodiment, the substrate and/or backinglayer comprises one or more water insoluble polymers. Suitable polymersinclude, but are not limited to, polyethylene terephthalate andpolyether ether ketone, polycarbonate, polyethylene, or other filmforming polymers amphiphilic polyurethanes, polyether polyurethane(PEU), polyetheretherketone (PEEK), and polyamide-imide (PAI). Furthersuitable polymers are described in U.S. Pat. No. 7,785,301, which isincorporated herein in its entirety. In another embodiment, the backinglayer and/or substrate is formed from an adhesive. One suitable adhesiveis the Dymax® 1187-M UV medical device adhesive. It will be appreciatedthat any biocompatible adhesive is suitable for use with, in and/or asthe backing layer and/or substrate. The backing layer and/or substratemay also be a nonwoven or porous film double coated with pressuresensitive adhesive. The substrate and/or backing layer may be rigid,substantially rigid or may be at least partially flexible to conform tothe surface of the patient's skin. In any case, the substrate and/orbacking layer should be sufficiently strong and/or rigid to assist in orallow for the microstructures to at least partially penetrate thepatient's skin. The substrate is typically substantially planar, but maybe contoured.

In reference to the microstructures themselves, in general, at least aportion of the microstructures have a height above the base or structurethat is sufficient to pierce at least a portion of the epidermis. Inembodiments, the microstructures have a height sufficient to pierce allor a portion of the stratum corneum. Typically, the microstructures havea height that penetrates into the epidermis where the density of nervereceptors is low. In embodiments, at least a portion of themicrostructures have a height of at least about 50 μm or at least about100 μm, or at least about 150 μm, or at least about 200 μm, or at leastabout 250 μm, or at least about 300 μm. In general, the microstructureshave a height of no more than about 1 mm, no more than about 500 μm, nomore than about 300 μm, no more than about 200 μm, or no more than about150 μm. In embodiments, the microstructures have a height of betweenabout 50 μm-1 mm. It will be appreciated that the microstructures withinan array may have different heights. The microstructures may have anaspect ratio (height to diameter at base) of at least 10:1, preferablyat least about 5:1, more preferably at least about 3:1, or at leastabout 2:1, or at least about 1:1. As the depth of the epidermis and/ordermis layers may be different depending on the area of the body, itwill be appreciated that the height of the microstructures may beadjusted depending on the administration site.

The microprojections may be spaced about 0-500 μm apart. In specific,but not limiting embodiments, the microprojections are spaced about 0μm, about 50 μm, about 100 μm, about 150 μm, about 200 μm, about 250 μm,about 300 μm, about 350 μm, about 400 μm, about 450 μm, or about 500 μmapart. The space between the microprojections may be measured from thebase of the microprojections (base to base) or from the tip (tip totip).

One illustrative shape for the microstructures is a cone with apolygonal bottom, for example, being hexagonal or rhombus-shaped.Additional microstructure shapes include those provided, for example, inU.S. Patent Publication No. 2004/0087992 with exemplary suitable shapesshown in FIGS. 10A-10B. In embodiments, at least a portion of themicrostructure shape may be substantially cylindrical, cone-shaped,funnel-shaped, or pyramidal. In further embodiments, at least a portionof the microstructures has an asymmetrical cross-dimensional shape.Suitable asymmetric shapes include, but are not limited to, rectangular,square, oval, elliptical, circular, rhombus, triangular, polygonal,star-shaped, etc. In some embodiments, the distal layer has across-dimension in one direction that is smaller than thecross-dimension in the other direction. Exemplary cross-dimensionalshapes with this configuration include, but are not limited to,rectangular, rhombus shaped, ellipse, and oval. The microstructurestypically, but not always, have a sharp, pointed or conical distal endto ease and/or facilitate penetration.

In the embodiments shown in FIGS. 10A-10B, at least a portion of themicrostructure has a funnel shape 40. In embodiments, the microstructurehas a funnel portion 40, a cylindrical portion 42, and a tip 44. In FIG.10A, the diameter of the microstructure is growing faster than linearfashion with respect to the distance from the distal end. Wheremicrostructures are thicker towards the base, a portion of themicrostructure adjacent to the base, which may be referred to herein asa “proximal portion” “backing portion”, “basement”, “foundation”, or asan “upper portion” may be designed not to penetrate the skin.

The proximal funnel shape allows for relatively larger volumes to bedispensed in the microstructure mold for a given total length of themicrostructure. The proximal funnel shape provides a larger volume (tofill) without requiring a proportional increase in microstructureheight, which results in a longer drug containing portion in themicrostructure. Thus, the proximal funnel shape allows for a largersolid volume for the distal portion of the microstructure with a singlefill of the mold. Other shapes may require several fill and dry cyclesto achieve the same amount of solid distal portion as one fill and drycycle for the funnel shaped microstructures.

While the array itself may possess any of a number of shapes, the arrayis generally sized to possess a diameter of from about 5 millimeters toabout 25 millimeters, or from about 7 to about 20 millimeters, or fromabout 8 to about 16 millimeters. Exemplary diameters include 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25millimeters.

At least a portion of the microstructures are typically formed of apolymer matrix comprising at least one therapeutic agent, active agent,or drug (collectively “agent” or “therapeutic agent” hereafter). Theagent to be administered can be one or more of any of therapeuticagents, active agents or drugs known in the art, and include the broadclasses of compounds such as, by way of illustration and not limitation:analeptic agents; analgesic agents; antiarthritic agents; anticanceragents, including antineoplastic drugs; anticholinergics;anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals;antihelminthics; antihistamines; antihyperlipidemic agents;antihypertensive agents; anti-infective agents such as antibiotics,antifungal agents, antiviral agents and bacteriostatic and bactericidalcompounds; antiinflammatory agents; antimigraine preparations;antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics;antipyretics; antispasmodics; antitubercular agents; antiulcer agents;anxiolytics; appetite suppressants; attention deficit disorder andattention deficit hyperactivity disorder drugs; cardiovascularpreparations including calcium channel blockers, antianginal agents,central nervous system agents, beta-blockers and antiarrhythmic agents;caustic agents; central nervous system stimulants; cough and coldpreparations, including decongestants; cytokines; diuretics; geneticmaterials; herbal remedies; hormonolytics; hypnotics; hypoglycemicagents; immunosuppressive agents; keratolytic agents; leukotrieneinhibitors; mitotic inhibitors; muscle relaxants; narcotic antagonists;nicotine; nutritional agents, such as vitamins, essential amino acidsand fatty acids; ophthalmic drugs such as antiglaucoma agents; painrelieving agents such as anesthetic agents; parasympatholytics; peptidedrugs; proteolytic enzymes; psychostimulants; respiratory drugs,including antiasthmatic agents; sedatives; steroids, includingprogestogens, estrogens, corticosteroids, androgens and anabolic agents;smoking cessation agents; sympathomimetics; tissue-healing enhancingagents; tranquilizers; vasodilators including general coronary,peripheral and cerebral; vessicants; and combinations thereof. In someembodiments, the agent is a protein or a peptide. In other embodiments,the agent is a vaccine.

Examples of peptides and proteins which may be used with themicrostructure arrays include, but are not limited to, parathyroidhormone (PTH), oxytocin, vasopressin, adrenocorticotropic hormone(ACTH), epidermal growth factor (EGF), prolactin, luteinizing hormone,follicle stimulating hormone, luliberin or luteinizing hormone releasinghormone (LHRH), insulin, somatostatin, glucagon, interferon, gastrin,tetragastrin, pentagastrin, urogastrone, secretin, calcitonin,enkephalins, endorphins, kyotorphin, taftsin, thymopoietin, thymosin,thymostimulin, thymic humoral factor, serum thymic factor, tumornecrosis factor, colony stimulating factors, motilin, bombesin,dinorphin, neurotensin, cerulein, bradykinin, urokinase, kallikrein,substance P analogues and antagonists, angiotensin II, nerve growthfactor, blood coagulation factors VII and IX, lysozyme chloride, renin,bradykinin, tyrocidin, gramicidines, growth hormones, melanocytestimulating hormone, thyroid hormone releasing hormone, thyroidstimulating hormone, pancreozymin, cholecystokinin, human placentallactogen, human chorionic gonadotropin, protein synthesis stimulatingpeptide, gastric inhibitory peptide, vasoactive intestinal peptide,platelet derived growth factor, growth hormone releasing factor, bonemorphogenic protein, and synthetic analogues and modifications andpharmacologically active fragments thereof. Peptidyl drugs also includesynthetic analogs of LHRH, e.g., buserelin, deslorelin, fertirelin,goserelin, histrelin, leuprolide (leuprorelin), lutrelin, nafarelin,tryptorelin, and pharmacologically active salts thereof. Administrationof oligonucleotides is also contemplated, and includes DNA and RNA,other naturally occurring oligonucleotides, unnatural oligonucleotides,and any combinations and/or fragments thereof. Therapeutic antibodiesinclude Orthoclone OKT3 (muromonab CD3), ReoPro (abciximab), Rituxan(rituximab), Zenapax (daclizumab), Remicade (infliximab), Simulect(basiliximab), Synagis (palivizumab), Herceptin (trastuzumab), Mylotarg(gemtuzumab ozogamicin), CroFab, DigiFab, Campath (alemtuzumab), andZevalin (ibritumomab tiuxetan).

In other embodiments, at least a portion of the distal layer comprisesan agent suitable for use as a prophylactic and/or therapeutic vaccine.Examples of vaccines include, but are not limited to, vaccines tovaricella, diphtheria, pertussis, hepatitis (A and/or B), HumanPapillomavirus, influenza, measles, mumps, rubella, whooping cough,polio, tetanus, meningitis, shingles, etc.

In another embodiment, at least a portion of the distal layer comprisesan agent suitable for veterinary uses. Such uses include, but are notlimited to, therapeutic and diagnostic veterinary uses,

In embodiments, the polymer matrix comprises at least about 10-50% ofthe therapeutic agent. In other embodiments, the polymer matrixcomprises at least about 45-50%, about 30-50%, about 25-50%, about20-50%, or about 15-50% of the therapeutic agent. In a furtherembodiment, the polymer matrix comprises at least about 10-50% of atleast one structural polymer. In specific, but not limiting embodiments,the polymer matrix comprises at least about 45-50%, about 30-50%, about25-50%, about 20-50%, or about 15-50% of at least one structuralpolymer. In embodiments, % is weight %.

In one aspect, the microstructure arrays described herein providesustained release or sustained delivery of the therapeutic agent. Inthis embodiment, the microstructure array typically comprises anapproximately planar substrate and a plurality of microstructurescontacting and being fixedly attached to a surface of the substrate. Atleast a portion of the microstructures are formed of a polymer matrixcomprising (i) at least one water insoluble, biodegradable polymer, and(ii) at least one therapeutic agent. In one embodiment, themicrostructures include a distal layer formed of the polymer matrix. Thepolymer matrix distal layer may be referred to as a drug-in-tip (DIT)distal layer. In another embodiment, the microstructures include adistal layer formed of the polymer matrix and a proximal or backinglayer formed of a non-biodegradable polymer. At least a portion of theproximal or backing layer may be configured so that it does notpenetrate the subject's skin.

Suitable water insoluble, biodegradable polymers are known in the art.Exemplary water insoluble, biodegradable polymers include, but are notlimited to, polylactide, α-hydroxy acids such as polylactic-co-glycolicacid (PLGA), polyanhydrides, an aliphatic polyester, a copolyester withaliphatic and aromatic blocks, a polyester amide, a polyester urethane,a polyethylene oxide polymer, a polyglycol, and co-polymers thereof. Forco-polymers, it will further be appreciated that the ratio of themonomers may be adjusted to achieve a desired hydrophobicity and/ordegradation rate. For example, lactide rich PLGA copolymers are morehydrophobic than glycolide rich PLGA copolymers. The ratio ofhydrophobic:hydrophilic monomers in the polymer may be selected toachieve the desired degradation rate. In one non-limiting embodiment,the water insoluble, biodegradable polymer is PLGA. In anotherembodiment, the PLGA has a lactic acid/glycolic acid ratio of 75/25.

Microneedle arrays are typically applied for a short period of time,which is sufficient to allow the water soluble polymer matrix DIT todegrade and release the drug, typically about 5-15 minutes. However,many drugs require a sustained deliver or slow delivery for properefficacy. Further, many conditions require continuous or sustainedlevels of a therapeutic agent for proper treatment. Slow release of adrug from a microprojection array may provide a suitable dose fortherapy over a period of time which avoids toxicity and/or side effects.In embodiments, the microarrays described herein provide for sustainedrelease or sustained delivery of the therapeutic agent from the polymermatrix, In embodiments sustained release provides for a slow and/orconstant release of the drug over an extended period of time. Sustainedrelease systems may be used to maintain constant drug levels over aperiod of time. In some embodiments, the microstructure arrays providefor release of the active agent from the polymer matrix for at least10-15 minutes. In other embodiments, the arrays provide for release ofthe active agent for at least about 15 minutes, at least about 30minutes, at least about 1 hour, at least about 2 hours, at least about 4hours, at least about 6 hours, at least about 8 hours, at least about 10hours, at least about 12 hours, at least about 18 hours, at least about24 hours, at least about 36 hours, at least about 48 hours, or longer.In one embodiment, the arrays provide for release of the active agentfor a period of at least about 15 minutes to about 60 hours. In furtherembodiments, the arrays provide for release of the active agent for aperiod of at least about 30 minutes to about 24 hours, about 1-48 hours,about 1-36 hours, about 1-24 hours, about 1-18 hours, about 1-12 hours,about 1-10 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours,about 1-2 hours, about 2-24 hours, about 2-18 hours, about 2-12 hours,about 2-10 hours, about 2-8 hours, about 2-6 hours, about 2-4 hours,about 4-24 hours, about 4-18 hours, about 4-12 hours, about 4-10 hours,about 4-8 hours, about 4-6 hours, about 6-24 hours, about 6-18 hours,about 6-12 hours, about 6-10 hours, about 6-8 hours, about 8-24 hours,about 8-18 hours, about 8-12 hours, about 8-10 hours, about 10-24 hours,about 10-18 hours, about 10-12 hours, about 12-24 hours, about 12-18hours, about 18-24 hours, about 1-144 hours, about 1-72 hours, about1-60, or longer. In further embodiments, the arrays provide for releaseof the active agent for a period of at least about 1-60 hours or longer,In specific, but not limiting embodiments, the therapeutic agent isreleased from the microstructure array for a period of at least about144 hours, about 72 hours, about 24 hours, about 12 hours, about 6hours, about 3 hours, about 2 hours, about 1 hour, or about 0.5 hours.

As described in Example 1, exemplary microstructure arrays comprising adrug-in-tip (DIT) distal layer comprising 35% Clonidine in PLGA and a UVadhesive backing layer on a PET substrate were formed and are shown inFIGS. 1A-1B. The DIT portions were highly degradable. As described inExample 2, a microstructure array comprising a 35% Clonidine in PLGA DITwas placed in acetonitrile (ACN) solvent to extract the DIT portion. Asseen in FIG. 2, the DIT portion dissolved in the solvent with the UVadhesive layer remaining.

It has been found that type of solvent used to fabricate PLGA DIT has asignificant effect on drug release rate. Without being limited as totheory, it is believed that the choice of solvent changes the morphology(crystalline/amorphous) of the drug, which affects the drug's releaserate. As described in Example 3, the effect of solvent choice on drugrelease rate was investigated by immersing microstructure arrays in aphosphate buffer, taking samples at specific time points and analyzingdrug content in the sample by HPLC. FIG. 5 is a graph of the % Clonidinereleased from the microstructure array over time in minutes. Arrays wereprepared using DMSO or ACN as the solvent for 44% Tamsulosin preparedwith DMSO (), 44% Clonidine prepared with DMSO (◯), 44% Clonidineprepared with ACN (▴), 30% Clonidine prepared with DMSO (Δ), and 30%Clonidine prepared with ACN (⋄). As it is shown in FIG. 5 Clonidineloaded MSA prepared from DMSO showed significantly lower drug releaserate as compared to Clonidine loaded MSA prepared from ACN. For the MSAwith a 44% Clonidine load, the MSA prepared with ACN had about a 15-20%increase in the percentage of drug released after 120 minutes and after360 minutes. For the MSA with a 30% Clonidine load, the MSA preparedwith ACN had about 40-45% increase in the percentage of drug releasedafter 120 minutes and about 30-35% increase after 360 minutes. On theother hand, Tamsulosin formulated with PLGA with DMSO as solvent hadalmost immediate drug release, probably due to the enhancedplasticization of the drug to the polymer by the DMSO solvent.

The physical state of the drug (e.g. crystalline or amorphous solidsolution) in PLGA DIT may have significant impact on drug releaseproperties of the matrix. Heat treatment may be used to change physicalstate of drug in PLGA DIT and thus drug release profile. Heat treatmentof dry PLGA DIT containing crystalline drug may lead to irreversibledissolution of crystals in solid PLGA if the samples are subjected toheating above drug melting point. To test this hypothesis PLGA filmsloaded with 35% Clonidine were prepared by casting from ACN (PLGAconcentration in liquid casting solution was 25%) on a microscope glass.After casting and drying at 70° C. (below Clonidine melting point)Clonidine crystals had been formed in the film as it is shown in theFIG. 6A. A spot in the obtained films was located and marked to tracechanges in the film after heat treatment. Films were heat treated inconvection oven at 110° C. for 1 hour and then stored in dry cabinet for10 days. As it is seen from FIG. 6B no Clonidine crystallization wasobserved after heat treatment and storage. The small bright particlesobserved in FIG. 6B correspond to microscope glass background as it isevidenced by the control photograph of microscope glass in FIG. 6C.

Addition of hydrophilic components into a hydrophobic polymer matrix cansignificantly change the drug release profile. In one non-limitingembodiment, the hydrophilic component is PEG-PLGA. As described inExample 5, microstructure arrays comprising Clonidine in a PLGA polymermatrix were prepared including 0%, 10%, 20%, or 40% of a PEG-PLGAhydrophilic component. The release rate of the arrays was determined byimmersing the array in a phosphate buffer and taking samples at specifictime points and analyzing drug content in the sample by HPLC. FIG. 9 isa graph of the release rate of the drug in μg/hr/cm² for microstructurearrays comprising 0% (⋄), 10% (□), 20% (◯), or 40% (Δ) of thehydrophilic component over time in hours. FIG. 9 demonstrates that theaddition of hydrophilic PEG-PLGA into a PLGA matrix, the release of aprotein from the MSA increases with the increase of hydrophiliccomponent in the matrix. Addition of 10% or 20% of the hydrophiliccomponent reduced or eliminated the initial burst of the drug. Additionof 40% of the hydrophilic component resulted in an initial burst whichtapered off for about 6 hours. Addition of 10% hydrophilic componentresulted in a flat release rate with no burst and sustained release forat least 24 hours. Addition of 20% of the hydrophilic component resultedin a low initial burst with a release rate of about 10-15 μg/hr/cm² andthen a flat release rate for at least 24 hours.

In embodiments, the polymer matrix comprises at least about 5-40% of thehydrophilic component. In further embodiments, the polymer matrixcomprises at least about 5-35%, about 5-30%, about 5-25%, about 5-20%,about 5-15%, about 5-10%, about 10-35%, about 10-30%, about 10-25%,about 10-20%, about 10-15%, about 15-35%, about 15-30%, about 15-25%,about 15-20%, about 20-30%, about 20-25%, about 25-35%, or about 25-30%of the hydrophilic component. In embodiments, % is weight %.

In another embodiment, the drug release rate profile may be modulated inorder to meet certain therapeutic requirements for the drug. It will beappreciated that modulating the drug release rate profile may bebeneficial for the sustained release microarrays described herein aswell as with known microarrays such as those described in U.S.Publication No. U.S. 2008/0269685 and U.S. 2011/0276028, among others.

Achieving long term zero-order release of drugs from a biodegradablepolymer matrix has been difficult to achieve. Release of drugs from thepolymer matrix is often characterized by a rapid initial release(“burst”) in the first few hours followed by a slow,diffusion-controlled release thereafter. However, many drugs, includingmany peptide therapeutics, can be toxic when administered with a burstinitial release rate. Further, reducing or preventing the initial burstand/or controlling the release of the drug at a constant rate allows theblood concentration of the drug to be maintained for a long period oftime. In one embodiment, the release rate is modulated to provide a flator substantially flat release for at least a period of time. In anotherembodiment, the release rate is flat or substantially flat for at leasta period of time with no or substantially no initial burst. In a furtherembodiment, the release rate is, less than 3 C_(max)-C_(min).

In embodiments, modulating the release rate comprises modulating therelease rate of the drug to between about 0.05-10%/minute. It will beappreciated that modulating the release rate may refer to the overallrelease rate and/or to an initial release rate. In other words, one orboth of the overall release rate or the initial release rate may bemodulated. In other embodiments, the release rate is modulated tobetween about 0.5-10%/minute, about 1-10%/minute, about 2-10%/minute,about 5-10%/minute, about 0.5-20%/minute, about 1-20%/minute, about2-20%/minute, or about 5-20%/minute. In specific, but not limitingembodiments, the release rate is modulated to about 0.05%/minute, about0.5%/minute, about 1%/minute, about 2%/minute, about 3%/minute, about4%/minute, about 5%/minute, about 6%/minute, about 7%/minute, about8%/minute, about 9%/minute, about 10%/minute, or about 20%/minute. Inembodiments, % is weight %.

In embodiments, modulating the release rate comprises modulating therelease rate of the drug to between about 0.25-40 μg/hr/cm². It will beappreciated that modulating the release rate may refer to the overallrelease rate and/or to an initial release rate. In other words, one orboth of the overall release rate or the initial release rate may bemodulated. In other embodiments, the release rate is modulated tobetween about 0.5-30 μg/hr/cm², about 2-40 μg/hr/cm², about 2-30μg/hr/cm², about 2-25 μg/hr/cm², about 2-20 μg/hr/cm², about 2-15μg/hr/cm², about 2-10 μg/hr/cm², about 2-8 μg/hr/cm², about 2-6μg/hr/cm², about 2-5 μg/hr/cm², about 2-4 μg/hr/cm², about 2-3μg/hr/cm², about 5-30 μg/hr/cm², about 5-25 μg/hr/cm², about 5-20μg/hr/cm², about 5-15 μg/hr/cm², about 5-10 μg/hr/cm², about 5-8μg/hr/cm², about 5-6 μg/hr/cm², about 10-40 μg/hr/cm², about 10-30μg/hr/cm², about 10-25 μg/hr/cm², about 10-20 μg/hr/cm², about 10-15μg/hr/cm², about 15-40 μg/hr/cm², about 15-30 μg/hr/cm², about 15-25μg/hr/cm², about 15-20 μg/hr/cm², about 20-30 μg/hr/cm², or about 20-25μg/hr/cm². In other embodiments, the release rate is modulated to belowabout 30 μg/hr/cm², about 20 μg/hr/cm², about 15 μg/hr/cm², about 10μg/hr/cm², about 8 μg/hr/cm², about 6 μg/hr/cm², or about 5 μg/hr/cm².

In even further embodiments, the initial release rate is adjusted ormodulated to about 0.25-10 μg/hr/cm², about 0.5-10 μg/hr/cm², about 1-10μg/hr/cm², about 2-10 μg/hr/cm², or about 1-10 μg/hr/cm².

In one embodiment, the polymer is a mixture or blend of low molecularweight polymers (LMWP) and high molecular weight polymers (HMWP). Theratio of LMWP to HMWP can be adjusted to modify the drug release rateprofile. The ratio of LMWP and HMWP may be adjusted to generate adesired release rate profile. In one preferred embodiment, the ratio ofLMWP and HMWP is adjusted to provide for a constant (e.g., zero-order)release of the drug. In another preferred embodiment, the ratio of LMWPand HMWP is adjusted to provide for a no-burst release of the drug. Inyet another embodiment, the ratio of LMWP and HMWP is adjusted to modifyor modulate the initial release rate of the drug without significantlyaffecting the sustained release rate.

Typically LMW biodegradable polymers degrade rapidly and polymermatrices formed from LMW polymers provide a rapid release rate for drugsdissolved or suspended in the matrix. Conversely, HMW biodegradablepolymers degrade more slowly and provide a slow release rate for drugsdissolved or suspended in a HMW polymer matrix. LMWP have lessentanglement than HMWP which typically have a more porous structure. Forblends of LMWP and HMWP, the LMWP can “plug” the free volume in the HMWPstructure.

The polymers used may possess a variety and range of molecular weights.In one embodiment, the LMWP has a molecular weight of about 1000-10K Da.In specific embodiments, the LMWP has a molecular weight of about 1000Da, about 2000 Da, about 3000 Da, about 4000 Da, about 5000 Da, about6000 Da, about 7000 Da, about 8000 Da, about 9000 Da, or about 10,000Da. In other embodiments, the LMWP has a molecular weight of about1000-5000 Da. In particular embodiment, the LMWP is polylactide having amolecular weight of about 1000 Da. In an embodiment, the HMWP has amolecular weight of about 50-300K Da. In other embodiments, the HMWP hasa molecular weight of about 50-70K Da. In further embodiments, the HMWPhas a molecular weight of about 200-300K Da. In specific, but notlimiting embodiments, the HMWP has a molecular weight of about 50K Da,about 60K Da, or about 70K Da.

Adjusting the blend or proportion of LMWP and HMWP in a hydrophobicpolymer matrix could significantly change the drug release profile. Asdescribed in Example 5, microstructure arrays comprising a drug in aPLGA polymer matrix were prepared including a 1:1 ratio of LMWP to HMWPor a 4:1 ratio of LMWP to HMWP. The HMWP had a molecular weight of about76K Da-120K Da. The release rate of the arrays was determined byimmersing the array in a phosphate buffer and taking samples at specifictime points and analyzing drug content in the sample by HPLC. FIG. 7 isa graph of the release rate of the drug in μg/hr/cm² for microstructurearrays comprising LMWP/HMWP of 1:1 (Δ) and LMWP/HMWP of 4:1 (□) overtime in hours. The 1:1 formulation had an initial burst of about 18-25μg/hr/cm². The 4:1 formulation had little to no initial burst with aninitial release rate of about 3-6 μg/hr/cm². The 1:1 formulation hadrelease of the drug for about 30 hours and the 4:1 formulation hadrelease of the drug for at least about 56 hours.

The release rate of the therapeutic agent may be modulated by the ratioof drug/polymer in the DIT matrix. The initial release rate of the drugis especially sensitive to this ratio. Different release rate profilescan be achieved by changing the drug/polymer ratio.

As shown in FIG. 8, a slower initial release and flatter release rateprofile is obtained with lower drug/polymer matrix ratio. The lowdrug/polymer ratio formulation had an initial release rate of about 5-8μg/hr/cm² while the high drug/polymer ratio formulation had an initialrelease rate of about 18-25 μg/hr/cm².

As described in Example 3, the effect of drug load and the ratio of drugto polymer on drug release rate was investigated by immersingmicrostructure arrays in a phosphate buffer, taking samples at specifictime points and analyzing drug content in the sample by HPLC. FIG. 4 isa graph of the % Clonidine released from the microstructure array overtime in minutes. Arrays were prepared having 44% Clonidine/10% PLGA (⋄)(including stirring), 44% Clonidine/10% PLGA (♦), 30% Clonidine/10% PLGA(□), 20% Clonidine/25% PLGA (Δ), and 15% Clonidine/25% PLGA (▴). The MSAwith a 44% and a 30% Clonidine drug load had about a 55% increase in thepercentage of drug released after 120 minutes over the 15% Clonidineloaded MSA. The MSA with a 44% or 30% Clonidine drug load had about a45% increase in the percentage of drug released after 240 minutes overthe 15% Clonidine loaded MSA. The MSA with a 44% or 30% Clonidine drugload had about a 30% increase in the percentage of drug released after360 minutes over the 15% Clonidine loaded MSA. The MSA with a 20%Clonidine drug load had about a 15-20% increase in the percentage ofdrug released after 120, 240, or 360 minutes over the 15% Clonidineloaded MSA. The MSA with a 44% and a 30% Clonidine drug load had about a35-40% increase in the percentage of drug released after 120 minutesover the 20% Clonidine loaded MSA. The MSA with a 44% or 30% Clonidinedrug load had about a 25% increase in the percentage of drug releasedafter 240 minutes over the 20% Clonidine loaded MSA. The MSA with a 44%or 30% Clonidine drug load had about a 10-15% increase in the percentageof drug released after 360 minutes over the 20% Clonidine loaded MSA.

As seen in FIG. 4, two formulations having 44% Clonidine/10% PLGA wereprepared. For one formulation (⋄), the release medium was stirred. Theformulation may be stirred constantly during release or at the time ofsampling. A mild shake was used for the second formulation (▴). As seenin FIG. 4, the release medium is substantially homogeneous with nosignificant drug concentration gradient build up around the releasingMSA for both methods.

As described in Example 5, microstructure arrays comprising Clonidine ina PLGA polymer matrix with a high drug to polymer ratio and a low drugto polymer ratio were prepared. The release rate of the arrays wasdetermined by immersing the array in a phosphate buffer and takingsamples at specific time points and analyzing drug content in the sampleby HPLC. FIG. 8 is a graph of the release rate of the drug in μg/hr/cm²for microstructure arrays comprising High Drug/Polymer Ratio (Δ) or LowDrug/Polymer Ratio (□) over time in hours. The array with the high drugto polymer ratio formulation had an initial burst of about 18-27μg/hr/cm². The low drug to polymer ratio formulation had little to noinitial burst with an initial release rate of about 5-7 μg/hr/cm². Thehigh drug to polymer ratio formulation had release of the drug for about32 hours and the low drug to polymer ratio formulation had release ofthe drug for at least about 56 hours.

In embodiments, the ratio of the drug to the polymer may be adjusted tomodulate the release rate of the drug from the polymer matrix. It willbe appreciated that the ratio of drug to polymer may be lower in orderto lower the release rate, especially for lowering the initial releaserate. It will further be appreciated that the ratio of drug to polymermay be higher in order to increase the release rate, especially forincreasing the initial release rate. In embodiments, either the ratio ofthe therapeutic agent to the polymer in the polymer matrix or the ratioof the polymer to the therapeutic agent in the polymer matrix is about1:1 to about 1:25. In further embodiments, the ratio is about 1:1-1:20,about 1:1-1:15, about 1:1-1:10, about 1:1-1:6, about 1:1-1:5, about1:1-1:4, about 1:1-1:3, about 1:1-1:2; about 1:2-1:25, about 1:2-1:20,about 1:2-1:15, about 1:2-1:10, about 1:2-1:6, about 1:2-1:5, about1:2-1:4, about 1:2-1:3, about 1:4-1:25, about 1:4-1:20, about 1:4-1:15,about 1:4-1:10, about 1:4-1:6, about 1:4-1:5. In specific non-limitingembodiments, the ratio of the therapeutic agent to the polymer in thepolymer matrix or the ratio of the polymer to the therapeutic agent inthe polymer matrix is about 1:1, about 1:2, about 1:3, about 1:4, about1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15,about 1:20, about 1:25, or greater.

It will be appreciated that the methods for modulating the release ratemay be combined without limitation. Specifically, the release rate maybe modulated or adjusted by any one of the combined or separate methodsdescribed herein including adding a hydrophilic component to the polymermatrix, adjusting the drug to polymer ratio in the polymer matrix, usinga blend of LMWP and HMWP and/or adjusting the ratio of the polymers inthe polymer matrix, the choice of solvent in preparing the polymermatrix, and/or a heat treatment.

In another aspect, the microstructure arrays provide an increased drugload. Many microstructure arrays include a DIT portion that penetratesthe skin and a proximal or backing layer that does not penetrate theskin. The drug load is limited by the volume of the DIT (or penetratedportion) of the microstructures, among other factors. Sustained releasedosage forms in particular may require a higher dose load in themicrostructure array as the drug is administered over an extended periodof time. In one embodiment, the dose load of microstructure arraysand/or dose delivered from the arrays is increased by modifying themethod of preparing the microstructure arrays and/or modifying themicrostructure array configuration. In another embodiment, the releaserate profile is modified by the microstructure arrays produced by themodified method.

Many previous microstructure arrays provide a DIT configuration wherethe drug is loaded in a penetrating portion (FIG. 11A). Modifying themicrostructure configuration to provide drug load in the entiremicrostructure portion (penetrating and non-penetrating portions) as inFIG. 11B or to provide drug load in the entire microstructure portion(penetrating and non-penetrating portions) as well as in at least aportion of a backing layer as in FIG. 11C provides a higher volume ofthe microstructure array with drug loaded.

The configurations of FIGS. 11B and 110 also provide for a sustainedrelease of the drug based. It will be appreciated that theconfigurations of FIGS. 11B and 11C may provide sustained release of atherapeutic agent for microstructure arrays for the sustained releasemicroarrays described herein as well as with known microarrays such asthose described in U.S. Publication No. U.S. 2008/0269685 and U.S.2011/0276028 among others.

Further, the configurations of FIGS. 11B (whole MS embodiment) and 11C(whole plus MS embodiment) can be used to modulate or tailor the drugrelease rate. In one embodiment, the whole MS or whole plus MSconfiguration is used to provide sustained drug release with or withoutan initial burst. It will be appreciated that the whole MS or whole plusMS configurations may be used with any one or all of the methods toadjust the drug release rate as described above.

As shown in FIG. 12A, many present microstructure arrays provide forrapid delivery of drug incorporated in the portion of themicrostructures that penetrate the skin. The penetrated portion maydissolve rapidly and release the drug rapidly. The array may then beremoved after a period of time applied on/in the skin, e.g. 5-15minutes. In one embodiment, the whole MS or whole plus MS configurationprovide an initial release of drug from the penetrated portion of themicrostructure and a sustained release from the non-penetratingportions. As seen in FIGS. 12B and 12C, the microstructure array withhigher drug load (whole MS as in FIG. 12B or whole plus MS as in FIG.120) is applied to the subject's skin. The penetrated portion of themicrostructure dissolves and releases the drug relatively rapidly. Thearray is left in place and the non-penetrated portion of themicrostructures of both the whole MS and whole plus MS configurationsdissolve and permeate into the skin. It will be appreciated thatchannels or pores formed by the administration of the microstructuresinto the skin will remain in the skin for a period of time after thepenetrating portion has dissolved. The drug dissolved from thenon-penetrating portion and/or the backing layer may thus be deliveredinto the stratum corneum. Depending on water back diffusion and drugpermeation into the skin, the non-penetrating portion and/or backinglayer may dissolve more slowly than the penetrating portion. Thus, thedrug release profile may be modified to deliver the drug at a slowerrate than delivered from the penetrating portion. It will be furtherappreciated that the penetrating portion, the non-penetrating portionand/or the backing layer may be modified to adjust the release rate, forexample by the methods described above. In other embodiments, thepenetrating portion is formed of a biodegradable, water soluble polymermatrix, as known in the art, and the non-penetrating portion and/orbacking layer is formed of a biodegradable, water insoluble polymermatrix as described above.

The microstructure arrays may be formed by any suitable means as knownin the art. A method of casting a microstructure array having drugloaded in the penetrating portions of the microstructures as shown inFIG. 11A is described in Example 7. In one embodiment, themicrostructure arrays are formed by dissolving an API and excipients inan aqueous buffer as described in Example 6. In embodiments, theexcipients may be any one of or any combination of a structure-formingpolymer, a sugar which can stabilize the API and/or plasticize thestructure-forming polymer, a surfactant and/or an antioxidant agent. Innon-limiting embodiments, the API can be polypeptides, such as humanparathyroid hormone (1-34) [(hPTH(1-34)] (MW 4118), proteins such ashuman growth hormone (hGH) (MW ˜22000), antibodies (MW˜150000), or avaccine with an antigen epitope conjugated on a carrier proteinformulated with or without adjuvant. Examples of the structure-formingpolymers are hydrophilic, water soluble polymers, such aspolysaccharides like Dextran 70, Dextran 40, Dextran 10, Hetastarch,Tetrastarch, cellulose derivatives, and other water soluble polymerslike polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol,copolymer of ethylene glycol and propylene glycol (Pluronic®), and/orblock copolymers of PLGA-PEG. Sugars can act as a stabilizing agent forbiological APIs like peptides, proteins, and antibodies, and/or can actas a plasticizer agent. Exemplary sugars include sorbitol, sucrose,trehalose, fructose, and/or dextrose. When Dextran, Hetastarch, and/orTetrastarch are used as the structure-forming polymer in the polymermatrix, sorbitol is a preferred sugar because it can not only stabilizethe API, but also plasticize the polymer matrix to make it less brittle.In some cases, a surfactant may be needed in the DIT formulation tochange the surface tension and/or reduce protein adsorption anddenaturation at interfaces. Exemplary surfactants include Polysorbate 20and Polysorbate 80. Some APIs may be susceptible to oxidation either inthe liquid DIT formulation or in solid DIT form. Exemplary antioxidantagents include, but are not limited to, methionine, cysteine, D-alphatocopherol acetate, EDTA, and/or vitamin E. Exemplary liquid castingformulations containing an API are provided in Table 1 and described inExample 6.

Example 8 describes a casting method for forming microstructure arrayswith drug loaded in the whole microstructure as shown in FIG. 11B.Briefly, about 70 μL of a liquid casting solution such as thosedescribed in Table 3 is dispensed on a mold having a plurality ofcavities therein, covered with a flat surface to spread the formulation,and the formulation is moved into the cavities. The liquid castingsolution has a solid content greater than 20% (w/w). When dried, thesolids fill a greater portion of the microstructures. The cavities maybe filled by pressurization or with a soluble gas such as CO₂ or CH₄.The mold is wiped and dried using two primary drying steps. The mold isfirst placed in a controlled humidity chamber having elevated humidity,about 10-95% RH, for 1-30 minutes at room temperature. In oneembodiment, the humidity in the chamber is controlled to 85% RH. Second,the mold is placed in an oven, such as an incubator oven, at 32° C. forabout 30 minutes. A backing layer formulation is cast on the dried drugformulation to connect the drug formulations. Exemplary backing layerformulations are provided in Table 4 in Example 6. The mold with backinglayer is dried in an oven for about 30-90 minutes. In one embodiment,the mold is dried in a convection oven. It will be appreciated that theoven may use any one of convection, conduction, or radiation for drying.In one embodiment, the mold is dried at an elevated temperature of about5-50° C. In one particular embodiment, the mold is dried in a convectionoven at about 45° C.

The whole MS microstructure arrays may also include a substrate asdescribed above. In Example 8, a UV adhesive is dispersed on the backinglayer, covered with a 5 mm sheet of polycarbonate (PC) film and curedusing a UV Fusion system. The array undergoes a final drying step undervacuum (about 0.05 torr) overnight. The final drying step may be at roomtemperature or at an elevated temperature, e.g. 35° C. The array isdemolded and die cut into 1-2 cm² arrays. The microstructure arrays maybe sealed in a storage container. In one embodiment, the MSAs are sealedindividually in a Polyfoil pouch. It will be appreciated that the pouchmay be sealed under nitrogen.

Example 9 describes a casting method for forming microstructure arrayswith drug loaded in the whole microstructure plus at least a portion ofthe backing layer as shown in FIG. 11C. Briefly, about 70 μL of a liquidcasting solution such as those described in Table 3 is dispensed on amold having a plurality of cavities therein. In one embodiment, asdescribed in Example 9, PET polymer disk with a circular opening isplaced on a silicone mold. About 50 μL of a liquid casting solution asdescribed in Table 3 in Example 6 is dispensed on the mold, covered witha flat surface to spread the formulation, and the formulation is movedinto the cavities/the cavities are filled. The cavities may be filled bypressurization or with a soluble gas such as CO₂ or CH₄. The mold iswiped and dried using two primary drying steps. The mold is placed in anoven, such as an incubator oven, at 5-50° C. The drug is loaded in thewhole microneedle and part of the backing layer. A backing layerformulation is cast on the dried drug formulation. Exemplary backinglayer formulations are provided in Table 4 in Example 6. The mold isdried in an oven for about 30-120 minutes. In one embodiment, the moldis dried at an elevated temperature of about 5-50° C. In one particularembodiment, the mold is dried in a convection oven at about 45° C. Themold may be placed in a compressed dry air box for about 30 minutes withcontrolled air flow before being placed in the oven.

In another embodiment, the drug layer and backing layer may befabricated in one step as illustrated in FIG. 13, In this embodiment,the mold preferably has an extended or elevated side to allow thecasting of the integrated microstructure and backing layer. The mold maybe formed with the sides or may include a barrier placed around thecavities on top of the mold. The casting formulation is dispensed in themold with elevated sides and dried to form the integrated microstructureand partial backing layer having a drug loaded therein. The mold isdried as described above, and a full backing layer is cast on thepartial backing layer.

The whole plus MS microstructure arrays may also include a substrate asdescribed above. In Example 9, a UV adhesive is dispersed on the backinglayer, covered with a 5 mm sheet of polycarbonate (PC) film and curedusing a UV Fusion system. The array undergoes a final drying step undervacuum (about 0.05 torr) overnight. The final drying step may be at roomtemperature or at an elevated temperature, e.g. 35° C. The array isdemolded and die cut into 1-2 cm² arrays. The microstructure arrays maybe sealed in a storage container. In one embodiment, the MSAs are sealedindividually in a Polyfoil pouch. It will be appreciated that the pouchmay be sealed under nitrogen.

Microstructure arrays with a whole plus MS configuration and comprisingPTH may be prepared in accord with Example 9. The MSA with the wholeplus MS configuration have a significantly higher drug load than DITmicrostructure arrays. The MSA with the whole plus MS configuration alsohave a significantly higher drug load than whole MS configuredmicrostructure arrays. The drug load for the whole plus MS PTH arrays isexpected to be about 450 μg/cm² for the whole plus MS configuration ascompared to 45-49 μg/cm² for the whole MS configuration and 32 μg/cm²for the DIT configuration. The drug load for the whole plus MSconfiguration increases by about 650-900% over the whole MSconfiguration and by about 420% for the DIT arrays for the PTH arrays.

B. Extended Wear Microstructure Arrays

In one embodiment, the present microarrays are suitable for extendedwear. Extended wear microarrays may be useful for sustained delivery ofdrugs or agents and/or to allow complete delivery of the drug or agent,e.g. to allow a biodegradable microstructure to degrade enough torelease all or most of the drug or agent. Improving adhesion between themicroarray and the subject's skin may improve or contribute to improvingdrug delivery efficiency. Microarrays are typically adhered to the skinto allow delivery of drugs by an adhesive layer around the perimeter ofthe microarray and/or by an adhesive backing that overlies and extendsbeyond the edge of the microarray. These methods may be unsuitable forextended wear applications as the microstructures are not secured to thesubject's skin and the array may pull-up or detach from the skin atleast in some in areas. This is especially likely for areas of themicroarray that are more removed from the perimeter adhesive such as thecenter of the array.

The microarrays of the present embodiment include at least one adhesiveto adhere the array to the skin for a desired period of time.Preferably, the adhesive is included as part of the microarray itself oris placed or available in the interior of microarray rather than beingapplied around a perimeter of the microarray. In one embodiment, themicrostructure array geometry is modified to allow an adhesive tocontact the skin in one or more locations in the microstructure arrayregion or interior. In a second embodiment, an adhesive layer isincluded in the microstructure array construct.

In one embodiment, the adhesive is a medical adhesive, tissue adhesiveand/or surgical adhesive. In other embodiments, the adhesive is amedical adhesive such as those used to attach medical devices to skin.Suitable medical adhesives include, but are not limited to acrylicadhesives, silicone based adhesives, hydrogel adhesives, and syntheticelastomer adhesives. In one embodiment tissue adhesive is a bioadhesivepolymer. Suitable tissue adhesives include, but are not limited to,cyanoacrylate polymers. Suitable cyanoacrylate polymers include, but arenot limited to, n-butyl-2-cyanoacrylate (e.g., Histoacryl®, PeriAcryl®),2-octyl cyanoacrylate (e.g. Dermabond®, SurgiSeal), and isobutylcyanoacrylate. In another embodiment, the adhesive is a fibrin sealant.In a further embodiment, the adhesive is a bioactive film. In a yetfurther embodiment, the adhesive is an acrylic pressure sensitiveadhesive. In even further embodiments, the adhesive is a rubber-basedadhesive. Preferably, the adhesive is nonirritating and/ornon-sensitizing. The adhesive may be selected based on tack and/or peelstrength as required to adhere the microstructure array to skin. In someembodiments, the adhesive is breathable.

It will be appreciated that the adhesive may require a further componentfor adhesion such as a two-part adhesive. In other embodiments, theadhesive adheres on contact with water or a moist surface. In yetfurther embodiments, the adhesive is activated by pressure, heat, light(UV or visible), biochemical reactions, or a combination of activationmethods. In an embodiment, the adhesive is a permanent adhesive. Inother embodiments, the adhesive is designed to reduce its adhesion overtime. In another embodiment, the adhesive reduces adhesion over time tomatch the expected wear period which permits easier removal of thearray. The adhesive may be absorbable or degradable, which has oneadvantage that the array is easily removed when the adhesive is absorbedor degraded.

In one embodiment, an adhesive coating is at least partially applied toat least a portion of the microstructures of the array. In embodiments,one or more adhesives are used to coat the microstructures. In otherembodiments, a portion of the microstructures are coated with oneadhesive and other microstructures are coated with a further adhesive.The microstructures may be alternatively coated or the coatings may beapplied in a pattern, For example, stronger adhesive may be alternatedwith a weaker adhesive. Alternatively, an absorbable adhesive may bealternated with one that is not so that the array is easier to removeyet remains attached until removed. It will be appreciated that thecoating may be applied over all or a portion of at least a portion ofthe microstructures in the array.

In embodiments, at least about 10%-100% of the microstructures in thearray are at least partially coated with an adhesive. In otherembodiments, at least about 25%-30%, about 25%-40%, about 25%-50%, about25%-60%, about 25%-70%, about 25%-75%, about 25%-80%, about 25%-90%,about 25%-95%, about 30%-100%, about 30%-40%, about 30%-50%, about30%-60%, about 30%-70%, about 30%-75%, about 30%-80%, about 30%-90%,about 30%-95%, about 40%-100%, about 40%-50%, about 40%-60%, about40%-70%, about 40%-75%, about 40%-80%, about 40%-90%, about 40%-95%,about 50%-100%, about 50%-60%, about 50%-70%, about 50%-75%, about50%-80%, about 50%-90%, about 50%-95%, about 60%-100%, about 60%-70%,about 60%-75%, about 60%-80%, about 60%-90%, about 60%-95%, about70%-100%, about 70%-75%, about 70%-80%, about 70%-90%, about 70%-95%,about 80%-100%, about 80%-90%, about 80%-95%, about 90%-100%, about90%-95%, about 90%-100%, or about 95%-100% of the microstructures in thearray are coated with an adhesive.

As shown in FIG. 14, at least a portion of the microstructures 10 arecoated with an adhesive coating 12. In one embodiment where themicrostructures include a DIT portion 16, at least the DIT portion iscoated with an adhesive. In other embodiments, only the backing layer,or at least a portion thereof, is coated with an adhesive.Alternatively, at least a portion of both the DIT portion 16 and thebacking layer 18 are coated with an adhesive. The adhesive coating maydirectly contact all or a portion of the microstructures.

The coating may be applied directly to the microstructures or may beseparated by a spacing and/or by an intermediate layer such as anintermediate polymer layer.

In one embodiment, the adhesive coating is porous to allow delivery ofat least the drug. The adhesive may additionally contain or beconfigured with perforations, openings, or holes in at least a portionof the coating 14. This embodiment may be useful for biodegradablemicrostructures and/or where the drug does not easily pass through theadhesive. The perforations or openings may be any size or shape suitablefor the drug and/or microstructure polymer to pass through. Theperforations may be formed by any suitable method. In one embodiment,the perforations are formed mechanically and/or chemically. In onenon-limiting embodiment, a portion of the coating is removed to form theperforations. In yet another embodiment, the perforations are formed bymasking the microstructures and spray coating or dip coating themicrostructure array and removing the masking agent. In a furtherembodiment where the coating is applied as part of a casting method, themicrostructure mold may be configured so that the resulting coatingincludes perforations or is otherwise non-continuous. For example, themold may include protrusions or other features within the mold interiorthat the coating does not cover. The resulting coating will benon-continuous, e.g. contain perforations or openings. In otherembodiments, the coating is otherwise non-continuous over at least aportion of the microstructure surface. In another embodiment, themicrostructures are spot coated with the adhesive.

In another embodiment, only a portion of each microstructure (of themicrostructures that are coated) is coated with an adhesive. In oneembodiment, at least a portion of the distal end of the microstructuresare coated. In another embodiment, at least a portion of the proximalend is coated. The coating may be selectively applied by any suitablemeans including, but not limited to, spray coating, dip coating, or beapplied during formation of the microstructures. It will further beappreciated that methods used to coat microneedles with a therapeuticagent, e.g. those described in U.S. Pat. No. 8,057,842, may also be usedto coat the microstructures with an adhesive. Where the microstructuresare formed by casting the microstructures in a mold, the adhesive may beadded at a point so that only the desired portion of the microstructureis coated. For example, where a portion of the distal tip is coated, thecoating may be added to the mold prior to adding the polymer matrix, ormatrices, of the microstructures. Where a portion of the proximal end iscoated, the coating may be added to the mold after the polymer matrixfor the distal tip is added. As shown in FIG. 15, the microstructure 10includes a partial adhesive coating 12 that covers the proximal portionof the microstructure. In this embodiment, the microstructure includes abiodegradable distal tip 16 and a non-biodegradable proximal portion 18.Only the proximal portion that is not biodegradable is covered by theadhesive coating. In this embodiment, it is not necessary to use aporous adhesive or include perforations in the coating as thebiodegradable portion is not coated. It will be appreciated that apartial coating may be porous and/or include non-continuous features asdescribed above. It will further be appreciated that only the outerportion or surface of the proximal portion 18 of the microstructures mayinclude the coating 12.

In embodiments, at least about 10%-100% of the microstructure is coated.In other embodiments, at least about 25%-30%, about 25%-40%, about25%-50%, about 25%-60%, about 25%-70%, about 25%-75%, about 25%-80%,about 25%-90%, about 25%-95%, about 30%-100%, about 30%-40%, about30%-50%, about 30%-60%, about 30%-70%, about 30%-75%, about 30%-80%,about 30%-90%, about 30%-95%, about 40%-100%, about 40%-50%, about40%-60%, about 40%-70%, about 40%-75%, about 40%-80%, about 40%-90%,about 40%-95%, about 50%-100%, about 50%-60%, about 50%-70%, about50%-75%, about 50%-80%, about 50%-90%, about 50%-95%, about 60%-100%,about 60%-70%, about 60%-75%, about 60%-80%, about 60%-90%, about60%-95%, about 70%-100%, about 70%-75%, about 70%-80%, about 70%-90%,about 70%-95%, about 80%-100%, about 80%-90%, about 80%-95%, about90%-100%, about 90%-95%, about 90%-100%, or about 95%-100% of themicrostructure is coated with an adhesive (of the microstructures thatare coated). It will be appreciated that these percentages apply both toembodiments that use a non-continuous adhesive coating and/or a partialadhesive coating.

In another embodiment, an adhesive coating is applied at least partiallybetween at least a portion of the microstructures in the array. In oneembodiment, the adhesive coating is applied to the substrate or backingbetween the microstructures. In another embodiment, as shown in FIG. 16,the coating is applied to the substrate or backing 20 between themicrostructures 10. In this embodiment, the coating may also be appliedat least partially to the proximal portion of the microstructures 21. Inthis non-limiting embodiment, the proximal portion 18 of themicrostructure is non-biodegradable and the distal portion 16 includingat least one agent is biodegradable. It will be appreciated that thecoating may be applied only to the substrate or backing 20 between themicrostructures. It will further be appreciated that the coating may beapplied to the substrate or backing and all of a non-biodegradableproximal portion, where present.

In another embodiment, the microstructure array is layered and includesan adhesive as one layer in the array. Exemplary embodiments where themicrostructure geometry includes an adhesive are shown in FIGS. 17A-17B.In this embodiment, the adhesive is included as a layer on the substrateor backing which includes at least one opening or hole that allows theadhesive to contact the subject's skin. It will be appreciated that thenumber and placement of the openings may be selected to provide thedesired adhesion. Placement of the openings may be selected according toa pattern to provide the desired adhesion of the microstructure array.The opening may be of any sufficient diameter for the adhesive tocontact the skin. A larger diameter results in more contact between theskin and the adhesive. One skilled in the art can calculate the contactnecessary, and therefore the required opening diameter, based at leastone the adhesive properties of the adhesive such as adhesion strength.

FIG. 17A shows two microstructures 26 of a microstructure array 22positioned on a substrate 20. The substrate includes a hole or opening24 positioned between the microstructures. An adhesive layer 28 ispositioned at least partially on the substrate on the surface oppositethe microstructures. The adhesive can travel through the opening tocontact the subject's skin. In one embodiment, pressure or another forceis applied to the adhesive layer to move at least a portion of theadhesive through the opening to contact the skin, In another embodiment,the adhesive is sufficiently fluid to flow through the opening. In otherembodiments, the adhesive may be altered to be sufficiently fluid toflow through the opening, e.g. by heating the adhesive, In yet anotherembodiment, the substrate layer is sufficiently thin and/or the openingis sufficiently large that the adhesive contacts the skin withoutflowing through the opening. The microstructure array may include afurther adhesive backing layer 30 that overlies and contains theadhesive. In other embodiments, the adhesive is an adhesive tape or adouble-sided adhesive coated nonwoven or porous film.

In another embodiment as shown in FIG. 178, the adhesive 28 may beapplied on the substrate 20 surface opposite the microstructures 26 asdiscrete portions at or near the opening(s) 24. As above, thisembodiment may include an adhesive backing 30 positioned at least overthe adhesive depots. One or more adhesives may be applied to thesubstrate. It will be appreciated that the adhesive applied at thedepots may be selected so as to provide a desired effect. For example, astronger adhesive may be alternated with a weaker adhesive.Alternatively, an absorbable adhesive may be alternated with one that isnot so that the array is easier to remove yet remains attached untilremoved.

FIGS. 18A-18B show a substrate 20 without openings (FIG. 18A) and with aplurality of openings 24 (FIG. 18B).

III. METHODS OF MAKING MICROSTRUCTURE ARRAYS

Before describing the methods of manufacture in detail, it is to beunderstood that the methods are not limited to specific solvents,materials, or device structures, as such may vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting.

Examples of forming various microstructure arrays having differentconfigurations are provided in Examples 1 and 4. In one exemplarymethod, an array is prepared by (a) filling a mold with cavitiescorresponding to the negative of the microstructures with a castingsolution comprising a biocompatible material such as a biocompatiblepolymer and a solvent, (b) removing the solvent, and (c) de-molding theresulting array from the mold. The solvent may be removed by anysuitable means including, but not limited, to drying the mold filledwith the casting solution in an oven. The casting solution preferablycontains an active agent or ingredient. In one or more embodiments, themicrostructures themselves comprise the active ingredient mixed, ordispersed in a polymer matrix, as opposed to having the activeingredient present as a coating on a microstructure or microneedle madeof a different, biocompatible material such as a metal. Typically,excess formulation is scraped or wiped from the mold surface prior todrying. Where the microstructures are not integral with a substrate orbacking layer, the microstructures are affixed to the substrate orbacking layer with an adhesive prior to de-molding. Further methods ofpreparing microstructure arrays are described in Examples 6-9.

IV. METHODS OF USE

The methods, kits, microstructure arrays and related devices describedherein may be used for treating any condition. It will be appreciatedthat the microstructure arrays may be used with any appropriateapplicator including the applicator described in U.S. Publication No.2011/0276027 as well as those described in Attorney Docket No.091500-0442 and 091500-0478, each of which are incorporated herein intheir entirety.

In one aspect, a method for applying the microarrays described hereinfor an extended period is provided. In embodiments, the extended wearmicroarrays are secured to the subject's skin for at least about 5minutes to 24 hours. In other embodiments, the extended wear microarraysare secured to the subject's skin for at least about 10 minutes to 24hours, at least about 15 minutes to 24 hours, at least about 30 minutesto 24 hours, at least about 1-24 hours, at least about 1-2 hours, atleast about 1-3 hours, at least about 1-4 hours, at least about 1-5hours, at least about 1-6 hours, at least about 1-8 hours, at leastabout 1-10 hours, at least about 1-12 hours, at least about 2-24 hours,at least about 2-3 hours, at least about 2-4 hours, at least about 2-5hours, at least about 2-6 hours, at least about 2-8 hours, at leastabout 2-10 hours, at least about 2-12 hours, at least about 3-24 hours,at least about 3-4 hours, at least about 3-5 hours, at least about 3-6hours, at least about 3-8 hours, at least about 3-10 hours, at leastabout 3-12 hours, at least about 4-24 hours, at least about 4-5 hours,at least about 4-6 hours, at least about 4-8 hours, at least about 4-10hours, at least about 4-12 hours, at least about 5-24 hours, at leastabout 5-6 hours, at least about 5-8 hours, at least about 5-10 hours, atleast about 5-12 hours, at least about 8-10 hours, at least about 10-24hours, at least about 10-12 hours, at least about 12-24 hours, orlonger. In specific, but not limiting embodiments, the microarray issecured to the subject's skin for at least about 5 minutes, 10 minutes,15 minutes, 30 minutes, 45 minutes, or longer. In other specific, butnot limiting embodiments, the microarray is secured to the subject'sskin for at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6hours, 8 hours, 10 hours, 12 hours, 18 hours, 24 hours, or longer. Inother embodiments, the extended wear microarrays are secured to thesubject's skin for at least about 1-30 days. In further embodiments, themicroarrays are secured to the subject's skin for at least about 1-2days, at least about 1-3 days, at least about 1-4 days, at least about1-5 days, at least about 1-7 days, at least about 10 days, at leastabout 1-14 days, at least about 1-21 days, or longer. In specific, butnot limiting embodiments, the microarray is secured to the subject'sskin for at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 10 days, 14 days, 21 days, 30 days, or longer.

In embodiments, the extended wear microarrays are secured to thesubject's skin until a desired portion of the total drug or agent doseis delivered. The portion of the total dose delivered may be determinedby any suitable method including without limitation a residual analysisof the device as known in the art. In other embodiments, the microarrayis secured to the subject's skin until at least about 10-100% of thetotal dose of drug in the array is delivered. In further embodiments,the microarray is secured to the subject's skin until at least about10-25%, about 10-50%, about 10-55%, about 10-60%, about 10-65%, about10-70%, about 10-75%, about 10-80%, about 10-90%, about 10-95%, or about10-99% of the total dose of drug in the array is delivered. In yetfurther embodiments, the microarray is secured to the subject's skinuntil at least about 25-50%, about 25-55%, about 25-60%, about 25-65%,about 25-70%, about 25-75%, about 25-80%, about 25-90%, about 25-95%,about 25-99%, about 50-55%, about 50-60%, about 50-65%, about 50-70%,about 50-75%, about 50-80%, about 50-90%, about 50-95%, about 50-99%,about 70-75%, about 70-80%, about 70-90%, about 70-95%, about 70-99%,about 75-80%, about 75-90%, about 75-95%, about 75-99%, about 80-90%,about 80-95%, about 80-99%, about 90-95%, about 90-99%, or about 95-99%of the total dose of drug in the array is delivered. In otherembodiments, the microarray is secure to the subject's skin until atleast about 25%, about 30%, about 55%, about 60%, about 65%, about 70%,about 75%, about 80%, about 90%, about 95%, or about 95% of the totaldose is delivered to the subject.

In another aspect, a method for administering an active agent ortherapeutic agent to a subject is provided. Preferably, the active ortherapeutic agent is administered dermally, transdermally, mucosally,and/or transmucosally. The method comprises providing a microprojectionarray or other delivery device comprising at least one active agent.Preferably, the microprojection array or other delivery device isconfigured to deliver at least one therapeutic agent. The agent may becoated on at least a portion of the microprojections and/or containedwithin at least a portion of the microstructures. The agent is delivereddermally, transdermally, mucosally, or transmucosally into contact withthe skin, or more generally a membrane or body surface, of a subject.

In one exemplary operation, an array is placed in contact with the skinand is adhered to the skin with an adhesive disposed at least partiallyon the microstructures or included as part of the array.

The array may be applied using an applicator as known in the art. Anexemplary applicator 32 is shown in FIG. 19. The applicator typicallyincludes a plunger or piston where the microstructure array ispositioned on a distal end of the plunger. An actuator or actuatingmember 34 is actuated to release the plunger. The plunger is typicallyheld in a constrained or restrained position until released. The plungerimpacts the skin and the microstructure array pierces or ruptures theskin surface. The microstructure array is removed from the plungerdistal end automatically or manually. The adhesive adheres themicrostructure array to the subject's skin for a desired period of time.

V. EXAMPLES

The following examples are illustrative in nature and are in no wayintended to be limiting. Efforts have been made to ensure accuracy withrespect to numbers (e.g., amounts, temperature, etc.) but some errorsand deviations should be accounted for. Unless indicated otherwise,parts are parts by weight, temperature is in ° C. and pressure is at ornear atmospheric.

Example 1 Casting Sustained Release Arrays

Poly(D,L-lactide-co-glycolide) (PLGA, L/G 75/25) (available from DurectCorporation (PN B6007-1P) was dissolved in acetonitrile (ACN) ordimethylsufoxide (DMSO) to a concentration of 10 wt % or 25 wt % to forma polymer solution.

Clonidine or Tamsulosin hydrochloride were placed in a 15 mLpolypropylene tube with the PLGA polymer solution. The drug wasdissolved in the PLGA polymer solution by warming the mixture in closedtubes for 10-15 minutes in a convection oven and vortexing until thedrug was completely dissolved. Formulations were prepared according toTable 1.

TABLE 1 PLGA/drug formulations % drug in solid % PLGA in liquidFormulation Drug DIT casting solution Solvent A1 Clonidine 44% 10% ACNA2 Tamsulosin 44% 10% DMSO A3 Clonidine 44% 10% DMSO A4 Clonidine 30%10% DMSO A5 Clonidine 30% 25% ACN A6 Clonidine 44% 25% ACN A7 Clonidine20% 25% ACN A8 Clonidine 15% 25% ACN

About 75 μL of liquid drug formulation was dispensed on a silicone basedmold, covered with 22 mm×30 mm glass cover slip to spread theformulation on the mold, and then pressurized at 50 psi for 1 minute.

The formulation was wiped and the mold dried in a convection oven at 70°C. for 1.5 hours.

UV adhesive was dispensed on the drug formulation in the mold, coveredwith a 5 mm polyethylene terephthalate (PET) film to spread the adhesiveand cured using a UV Fusion system. The UV curing dose was 1.6 J/cm².After curing, the microstructure (drug in tip distal layer and UVadhesive proximal layer on PET) was die cut with an 11 mm punch.

The resulting microstructures were inspected under microscope. Images ofintact microstructure arrays with Clonidine (35% drug in PLGA DIT) areshown in FIGS. 1A-113.

Example 2 Dissolution of Arrays

Microstructure arrays (MSA) comprising 35% Clonidine in PLGA DIT wereprepared in accord with Example 1 were treated with acetonitrile toextract the PLGA DIT tips and then were inspected under microscope toobserve the remaining stubs, which comprised the UV adhesive layer withan image taken from the sharp side of the microstructures shown in FIG.2.

Example 3 Drug Release from Microstructure Arrays

Microstructure arrays comprising Clonidine or Tamsulosin were preparedin accord with Example 1. The microstructure arrays were immersed inclosed 20 mL scintillation vials containing 10 mL phosphate buffer(pH=7.5, 10 mM) at 37° C. under mild shaking. At specified time points,1 mL of release medium was removed for drug content analysis by HPLC.The sample was substituted with 1 mL of fresh buffer.

After release experiments, the samples were inspected under amicroscope. Swelling of PLGA DIT portions was observed after exposurefor 1 week to phosphate buffer at 37° C. as shown in FIG. 3. It istheorized that the swelling of DIT after 1 week at 37° C. may be due tothe void left from the release of the drug from the PLGA matrix andpartial degradation of PLGA, which makes the polymer more hydrophilic.

The effect of Clonidine loading in PLGA DIT on cumulative drug releaseis shown in FIG. 4. Kinetic parameters, initial drug release rate (Δ%min) and time for the half drug released (t_(50%)), which was calculatedfrom the initial slope of the release curve, for the formulations shownin Table 1 are shown in Table 2. The Clonidine release rate decreasedsignificantly with decreasing Clonidine load in the PLGA formulation.

TABLE 2 Drug Release Parameters Initial Release Rate Total drug releasedFormulation (Δ% min) t_(50%) (min) mcg/array A1 1.85 27 126 A2 9.36 5139 A3 0.79 63 80.4 A4 0.28 181 32.7 A5 1.9 27 57.5 A6 1.9 27 78 A7 0.39128 87.3 A8 0.24 207 83.5

The type of solvent used to fabricate the PLGA DIT had a significanteffect on the drug release rate. As shown in FIG. 5, Clonidine loadedarrays prepared using a DMSO solvent showed a significantly lower drugrelease rate as compared to Clonidine loaded arrays prepared using ACN.Tamsulosin loaded arrays prepared using a DMSO solvent had almostimmediate drug release, which is likely due to the enhancedplasticization of the drug to the polymer by the DMSO solvent.

Example 4 Effect of Heat Treatment on Drug Crystallization in PLGA Films

PLGA films loaded with 35% Clonidine were prepared by casting from ACN(PLGA concentration in liquid casting solution was 25%) on a microscopeglass. The films were dried at 70° C. (which is below the melting pointfor Clonidine). An image of the film after casting and drying is shownin FIG. 6A, which shows Clonidine crystals formed in the film.

A spot in the films was marked to trace changes in the film. Films wereheat treated in a convection oven at 110° C. for 1 hour and then storedin a dry cabinet for 10 days. FIG. 6B shows no Clonidine crystallizationobserved after heat treatment and storage. The small, bright particlesobserved in the image correspond to microscope glass background asevidenced by the control photograph of a microscope glass shown in FIG.6C.

Example 5 Modulating Microstructure Array Release Profiles

Poly(DL lactide-co-glycolide) (PLGA, L/G 75/25) (available from DurectCorporation (PN B6007-1P, IV 0.55-0.75) was used as a high molecularweight polymer (HMWP) and PLGA (UG 75/25) from SurModics (1A, IV 0.1)was used as a low molecular weight polymer (LMWP).

PLGA was dissolved in acetonitrile (ACN) or dimethylsufoxide (DMSO) to aconcentration of 10 wt % or 25 wt % to form a polymer solution.

Clonidine or Tamsulosin hydrochloride were placed in a 15 mLpolypropylene tube with the PLGA polymer solution. The drug wasdissolved in the PLGA polymer solution by warming the mixture in closedtubes for 10-15 minutes in a convection oven and vortexing until thedrug was completely dissolved.

About 75 μL of liquid drug formulation was dispensed on a silicone basedmold, covered with 22 mm×30 mm glass cover slip to spread theformulation on the mold, and then pressurized at 50 psi for 1 minute.

The formulation was wiped and the mold dried in an oven at 32° C. for 30minutes, then dried at 50° C. under vacuum overnight.

UV adhesive was dispensed on the drug formulation in the mold, coveredwith a 5 mL polyethylene terephthalate (PET) or polycarbonate (PC) filmto spread the adhesive and cured using a UV Fusion system. The UV curingdose was 1.6 J/cm². After curing, the microstructure (drug in tip distallayer and UV adhesive proximal layer on PET) was die cut with an 11 or16 mm punch. The resulting microstructures were inspected undermicroscope and further vacuum dried at 35° C. overnight to remove anyresidual solvent.

A. In Vitro Release Rate

An in vitro release test was performed by immersing a microstructurearray in a closed 20 mL scintillation vials containing 10 mL PBS buffer(pH=7.4) containing 0.1% Polysorbate 20, which was added at time=0. Thevial was shaken at 100 rpm on an orbital shaking platform in anincubator at 37° C. One mL of release medium was removed atpredetermined time points to quantify drug release. Fresh release mediumwas replenished to maintain the volume of the release medium.

B. Effect of LMWP/HMWP Ratio on Release Rate

Microstructure arrays were prepared using 1:1 LMWP/HMWP or 4:1 LMWP/HMWPfor the polymer solution. An in vitro release test as above wasperformed with the results shown in FIG. 7.

C. Effect of Drug to Polymer Ratio on Release Rate

Microstructure arrays were prepared with a high drug/polymer ratio orlow drug/polymer ratio. An in vitro release test as above was performedwith the results shown in FIG. 8.

D. Effect of a Hydrophilic Component on Release Rate

Microstructure arrays were prepared in accord with the above method withthe addition of 10%, 20%, or 40% of a hydrophilic PEG-PLGA component. Anin vitro release test as above was performed with the results shown inFIG. 9.

Example 6 Casting Formulations

Liquid casting formulations are prepared by dissolving an activepharmaceutical ingredient (API) and excipients in an aqueous buffer asshown in Table 3.

TABLE 3 Liquid Casting Solution Formulations Formu- Polymer Sugar APIPS20 EDTA lation Type Wt % Type Wt % Type Wt % Wt % mg/mL B1 Dextran 7014 Sorbitol 5 PTH 1.8 NA NA B2 Dextran 70 10 Sorbitol 4 PTH 1.8 NA NA B3Dextran 70 27 Sorbitol 9 PTH 1.8 NA NA B4 Dextran 70 21 Sorbitol 7.5 PTH1.8 NA NA B5 Tetrastarch 14 Sorbitol 7 PTH 1.8 NA NA B6 Tetrastarch 10Sorbitol 5 PTH 1.8 NA NA B7 Hetastarch 14 Sorbitol 7 PTH 1.8 NA NA B8Hetastarch 10 Sorbitol 5 PTH 1.8 NA NA B9 Dextran 40 14 Sorbitol 5 PTH1.8 NA NA B10 Dextran 70 14 Sorbitol 5 PTH 2.8 NA NA B11 PVA 14 Sucrose5 PTH 2.8 NA NA

Different polymeric solutions may be used for casting a basement orbacking layer for the microstructure arrays. Liquid formulations for abacking layer are prepared by dissolving one or more polymers in asolvent or solvent mixture at or about room temperature with a polymerconcentration of about 10-40% by weight. Liquid formulations for castinga backing layer are prepared according to Table 4.

TABLE 4 Liquid Backing Layer Formulations Polymer Solvent FormulationType Wt % Type Wt % C1 Eudragit EPO 100 20 Ethanol/IPA (3:1) 80 C2Eudragit EPO 100 30 Ethanol/IPA (3:1) 70 C3 Eudragit EPO 100/PVP 20Ethanol/IPA (3:1) 80 (1:1) C4 PLGA (75/25) 10 Ethyl acetate 90 C5 PLGA(75/25) 15 Ethyl acetate 85 C6 PLGA (75/25) 25 Acetonitrile 75 C7 PLGA(75/25) 35 Acetonitrile 65 C8 PLGA (65/35) 20 Acetonitrile 80 C9 PLGA(65/35) 30 Acetonitrile 70  C10 PLA 20 Acetonitrile 80

Example 7 Casting Microstructure Arrays with Drug in Penetrating Portion

About 70 μL of liquid casting solution formulation number B1 wasdispensed on a silicone mold having diamond shaped cavities (200 μmlength, base width 70 μm, and 200 μm needle to needle spacing), coveredwith a 22 mm×30 mm glass cover slip to spread the formulation on themold, and then pressurized at 50 psi for 1 minute. The filled volume ofliquid casting solution formulation was about 1.5-2.0 μl/cm². The solidcontent of the liquid formulations was less than 20% (w/w).

The formulations were wiped and the mold dried in a controlled humiditychamber with elevated humidity such as 85% RH for 1-30 minutes at roomtemperature. The mold was then placed in an incubator oven at 32° C. forabout 30 minutes.

Backing layer formulation C6 was cast on the mold to connect the driedcasting formulation in the cavities. The mold was dried in a compresseddry air (CDA) box for 30 minutes with controlled air flow and then in aconvection oven at 45° C. for 30-90 minutes.

A second layer of backing layer formulation may be cast on the mold, andthe mold additionally dried in a compressed dry air (CDA) box for 30minutes with controlled air flow and then in a convection oven at 45° C.for 30-90 minutes.

UV adhesive was dispensed on the backing layer, covered with a smallsheet of 5 mm polycarbonate (PC) film to spread the adhesive and curedusing a UV Fusion system. The UV curing dose was 1.6 J/cm², Aftercuring, the microstructure array (drug in tip distal layer/PLGA backinglayer/UV adhesive substrate on PC backing) was removed from the mold anddie cut into 1-2 cm² arrays.

The microstructure array was dried to remove residual moisture from thedrug distal layer and residual solvent from the backing layer. The moldwas dried under vacuum (˜0.55 torr) at 35° C. or room temperatureovernight. The drug load for PTH was 32 μg/cm².

Example 8 Casting Microstructure Arrays with Increased Drug Load

About 70 μL of liquid casting solution formulation number B3 or B4 wasdispensed on a silicone mold having diamond shaped cavities (200 μmlength, base width 70 μm, and 200 μm needle to needle spacing), coveredwith a 22 mm×30 mm glass cover slip to spread the formulation on themold, and then pressurized at 50 psi for 1 minute. The filled volume ofliquid casting solution formulation in the mold was about 2.5-3.3μl/cm². The solid content of these liquid formulations was greater than20% (w/w) so solids can fill the cavities beyond the portion of theresulting microstructures that will penetrate skin when the distal layeris dried.

The formulations were wiped and the mold dried in a controlled humiditychamber with elevated humidity such as 85% RH for 1-30 minutes at roomtemperature. The mold was then placed in an incubator oven at 32° C. forabout 30 minutes.

Backing layer formulation C6 was cast on the mold to connect the driedcasting formulation in the cavities. The mold was dried in a CDA box for30 minutes with controlled air flow and then in a convection oven at 45°C. for 30-90 minutes.

UV adhesive was dispensed on the backing layer, covered with a smallsheet of 5 mm polycarbonate (PC) film to spread the adhesive and curedusing a UV Fusion system. The UV curing dose was 1.6 J/cm². Aftercuring, the microstructure array (drug in tip distal layer/PLGA backinglayer/UV adhesive substrate on PC backing) was removed from the mold anddie cut into 1-2 cm² arrays.

The microstructure array was dried to remove residual moisture from thedrug distal layer and residual solvent from the backing layer. The moldwas dried under vacuum (˜0.55 torr) at 35° C. or room temperatureovernight. Exemplary drug loads for the drug distal layer are listed inTable 5.

TABLE 5 Microstructure Array Drug Load for Drug Distal Layer Liquid LoadLiquid DIT Volume Drug load MSA Formulation API (μL/cm²) μg/cm² MSA D1B3 PTH 3.3 59 D2 B4 PTH 2.5 45 D3 B4 PTH 3.3 59

Example 9 Casting Microstructure Arrays with Drug in Penetrating Portionand Backing Layer

A PET disk with a circular opening area of about 2 cm² is placed on asilicone mold having diamond shaped cavities (200 μm length, base width70 μm, and 200 μm needle to needle spacing). To this circular area,about 50 μL of liquid casting solution formulation is dispensed on asilicone mold, covered with a 22 mm×30 mm glass cover slip to spread theformulation on the mold, and then pressurized at 50 psi for 1 minute.

The mold is then placed in an incubator oven at 32° C. for about 30minutes.

Backing layer formulation is cast on top of the dried drug containinglayer in the mold. The mold is dried in a CDA box for 30 minutes withcontrolled air flow and then in a convection oven at 45° C. for 30-90minutes.

UV adhesive is dispensed on the backing layer, covered with a smallsheet of 5 mm polycarbonate (PC) film to spread the adhesive and curedusing a UV Fusion system. The UV curing dose was 1.6 J/cm². Aftercuring, the microstructure array (drug in tip distal layer and partialbacking layer/PLGA backing layer/UV adhesive substrate on PC backing) isremoved from the mold and is die cut into 1-2 cm² arrays.

The microstructure array is dried to remove residual moisture from thedrug layer and residual solvent from the backing layer. The mold isdried under vacuum (˜0.55 torr) at 35° C. or room temperature overnight.

Example 10 In Vivo Skin Penetration Efficiency and Apparent DoseDelivery Efficiency

Microstructure arrays (MSAs) comprising PTH were prepared in accord withExample 8. MSAs were applied to shaved skin sites of rats or pigs usinga custom made applicator and held in situ (either manually by hand orwith skin contact adhesive) for a period time (e.g., 1-5 minutes). Afterremoving the applicator, the MSAs were kept on the animals for 5 minutesor 2 hours.

Residual drug remaining in the MSA was extracted by immersing the usedMSA in an aqueous extraction medium for ˜30 min and assayed using anappropriate analytical method, e.g. SEC-HPLC. The apparent delivereddose per unit, and delivery efficiency are then calculated as followswith the results shown in Table 6:

Apparent delivered dose=Initial drug load−Residual drug

% Drug delivery efficiency=100×Apparent delivered dose/Initial drug load

TABLE 6 Apparent Dose Delivered Apparent Dose (μg/cm²) MSA API Animal 5min wear 2 hr wear D1 PTH Rat 45 60 D2 PTH Pig 48 64

For MSAs with drug loaded in the entire microneedle, the apparent dosedelivered increases with increasing wear time, a phenomenon that wasobserved in both rats and pigs. Table 6 shows the apparent dosedelivered in vivo for hPTH(1-34) MSA after 5 min and 2 hour wear times.Apparent dose delivered increased with wear time by 33% for PTH in ratsand pigs.

Example 11 In Vivo Pharmacokinetics

Microstructure arrays (MSAs) comprising a protein are prepared in accordwith Example 8. MSAs are applied to shaved skin sites of rats or pigsusing a custom made applicator and held in situ (either manually by handor with skin contact adhesive) for a period time (e.g., 1-5 minutes).After removing the applicator, the MSAs are kept on the animals for 5minutes or 2 hours. The serum concentration PK profiles may be plottedby taking blood samples at predetermined times (e.g. 0.5, 1, 2, 3, 4, 5,6, 7, 8, 9, 10 hours etc.) and determining the serum concentration ofthe API. It is expected that serum concentrations of the API will behigher for the 2 hr wear compared to the 5 min wear. The overallsystemic exposure should correspond to the mean apparent doses achievedby the wear time. Thus, where the wear time for 5 min. vs. 2 hoursresults in a double in the mean apparent dose, the overall systemicexposure, e.g. represented by area under the curve (AUC), should alsoincrease or even double. Increasing the MSA wear time can increaseoverall systemic drug delivery

1. A microstructure apparatus, comprising:

an approximately planar substrate having a first surface and a secondsurface opposed thereto; and

a microstructure array comprising a plurality of microstructurescontacting the first surface of the substrate and fixedly attachedthereto, the microstructures being formed of a polymer matrix comprising(i) a water insoluble, biodegradable polymer, and (ii) at least onetherapeutic agent;

wherein release of the therapeutic agent from the polymer matrix issustained for a period of at least about 1-144 hours.

2. The microstructure apparatus of embodiment 1, wherein the waterinsoluble polymer is selected from polylactide, polyglycolide, andco-polymers thereof.3. The microstructure apparatus of the combined or separate embodiments1-2, wherein the polymer matrix comprises about 1-50% therapeutic agent.4. The microstructure apparatus of the combined or separate embodiments1-3, wherein the polymer matrix comprises about 10-50% therapeuticagent.5. The microstructure apparatus of the combined or separate embodiments1-4, wherein the polymer matrix comprises about 20-50% therapeuticagent.6. The microstructure apparatus of the combined or separate embodiments1-5, wherein the polymer matrix comprises about 25-50% therapeuticagent.7. The microstructure apparatus of the combined or separate embodiments1-6, wherein the polymer matrix comprises about 30-50% therapeuticagent.8. The microstructure apparatus of the combined or separate embodiments1-7, wherein the polymer matrix comprises about 45-50% therapeuticagent.9. The microstructure apparatus of the combined or separate embodiments1-8, wherein the polymer matrix comprises about 50-99% of the waterinsoluble, biodegradable polymer.10. The microstructure apparatus of the combined or separate embodiments1-9, wherein the polymer matrix comprises about 50-90% of the waterinsoluble, biodegradable polymer.11. The microstructure apparatus of the combined or separate embodiments1-10, wherein an initial release rate of the therapeutic agent from thepolymer matrix is between about 0.05-10%/minute.12. The microstructure apparatus of the combined or separate embodiments1-11, wherein an initial release rate of the therapeutic agent from thepolymer matrix is between about 0.5-10%/minute.13. The microstructure apparatus of the combined or separate embodiments1-12, wherein an initial release rate of the therapeutic agent from thepolymer matrix is between about 1-10%/minute.14. The microstructure apparatus of the combined or separate embodiments1-13, wherein an initial release rate of the therapeutic agent from thepolymer matrix is between about 2-10%/minute.15. The apparatus of the combined or separate embodiments 1-14, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 144 hours.16. The apparatus of the combined or separate embodiments 1-15, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 72 hours.17. The apparatus of the combined or separate embodiments 1-16, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 24 hours.18. The apparatus of the combined or separate embodiments 1-17, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 12 hours.19. The apparatus of the combined or separate embodiments 1-18, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 6 hours.20. The apparatus of the combined or separate embodiments 1-19, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 3 hours.21. The apparatus of the combined or separate embodiments 1-20, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 1 hour.22. The apparatus of the combined or separate embodiments 1-21, whereinthe microstructures are detachable from the substrate.23. The apparatus of the combined or separate embodiments 1-22, whereinthe therapeutic agent is selected from a drug, a small molecule, apeptide or protein, or a vaccine.24. A microstructure apparatus, alone or combined with any of theembodiments herein, comprising:

an approximately planar substrate having a first surface and a secondsurface opposed thereto; and

a microstructure array comprising a plurality of microstructurescontacting the first surface of the substrate and fixedly attachedthereto, the microstructures being formed of a polymer matrix comprising(i) at least one low molecular weight polymer, (ii) at least one highmolecular weight polymer, and (iii) at least one therapeutic agent;

wherein an initial release rate of the therapeutic agent from thepolymer matrix is between about 0.05-10%/minute;

wherein release of the therapeutic agent from the polymer matrix issustained for a period of at least about 1-144 hours.

25. The apparatus of embodiment 24, wherein the polymer matrix comprisesat least one water insoluble, biodegradable polymer.26. The apparatus of the combined or separate embodiments 24-25, whereinat least one of the low molecular weight polymer or the high molecularweight polymer is the water insoluble, biodegradable polymer.27. The apparatus of the combined or separate embodiments 24-26, whereinthe water insoluble, biodegradable polymer is selected from polylactide,polyglycolide, and co-polymers thereof.28. The apparatus of the combined or separate embodiments 24-27, whereinthe initial release rate is between about 0.5-10%/minute.29. The apparatus of the combined or separate embodiments 24-28, whereinthe initial release rate is between about 1-10%/minute.30. The apparatus of the combined or separate embodiments 24-29, whereinthe initial release rate of the therapeutic agent from the polymermatrix is less than about 1-10%/minute.31. The apparatus of the combined or separate embodiments 24-30, whereinthe low molecular weight polymer has a molecular weight of between about1-10K Da.32. The apparatus of the combined or separate embodiments 24-31, whereinthe high molecular weight polymer has a molecular weight of betweenabout 50-300K Da.33. The apparatus of the combined or separate embodiments 24-32, whereinthe high molecular weight polymer has a molecular weight of betweenabout 50-70K Da.34. The apparatus of the combined or separate embodiments 24-33, whereinthe low molecular weight polymer and high molecular weight polymers arepresent in a ratio of about 1:1-1:10.35. The apparatus of the combined or separate embodiments 24-34, whereinthe low molecular weight polymer and high molecular weight polymers arepresent in a ratio of about 1:1.36. The apparatus of the combined or separate embodiments 24-35, whereinthe low molecular weight polymer and high molecular weight polymers arepresent in a ratio of about 1:4.37. The apparatus of the combined or separate embodiments 24-36, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 144 hours.38. The apparatus of the combined or separate embodiments 24-37, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 72 hours.39. The apparatus of the combined or separate embodiments 24-38, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 24 hours.40. The apparatus of the combined or separate embodiments 24-39, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 12 hours.41. The apparatus of the combined or separate embodiments 24-40, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 6 hours.42. The apparatus of the combined or separate embodiments 24-41, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 3 hours.43. The apparatus of the combined or separate embodiments 24-42, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 1 hour.44. The apparatus of the combined or separate embodiments 24-43, whereinthe microstructures are detachable from the substrate.45. The apparatus of the combined or separate embodiments 24-44, whereinthe therapeutic agent is selected from a drug, a small molecule, apeptide or protein, or a vaccine.46. A microstructure apparatus, comprising:

an approximately planar substrate having a first surface and a secondsurface opposed thereto; and

a microstructure array comprising a plurality of microstructurescontacting the first surface of the substrate and fixedly attachedthereto, the microstructures being formed of a polymer matrix comprising(i) at least one biodegradable polymer, (ii) a hydrophilic component,and (iii) at least one therapeutic agent;

wherein release of the therapeutic agent from the polymer matrix issustained for a period of at least about 1-144 hours.

47. The apparatus of embodiment 46, wherein the biodegradable polymer isa water insoluble, biodegradable polymer.48. The apparatus of the combined or separate embodiments 46-47, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 4-24 hours.49. The apparatus of the combined or separate embodiments 46-48, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 4-8 hours.50. The apparatus of the combined or separate embodiments 46-49, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 144 hours.51. The apparatus of the combined or separate embodiments 46-50, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 72 hours.52. The apparatus of the combined or separate embodiments 46-51, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 24 hours.53. The apparatus of the combined or separate embodiments 46-52, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 12 hours.54. The apparatus of the combined or separate embodiments 46-53, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 6 hours.55. The apparatus of the combined or separate embodiments 46-54, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 3 hours.56. The apparatus of the combined or separate embodiments 46-55, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 1 hour.57. The apparatus of the combined or separate embodiments 46-56, whereinthe polymer matrix comprises about 5%-40% of the hydrophilic component.58. The apparatus of the combined or separate embodiments 46-57, whereinthe polymer matrix comprises about 5%-10% of the hydrophilic component.59. The apparatus of the combined or separate embodiments 46-58, whereinthe polymer matrix comprises about 5%-40% of the hydrophilic component.60. The apparatus of any the combined or separate embodiments 46-59,wherein the polymer matrix comprises up to about 40% of the hydrophiliccomponent.61. The apparatus of the combined or separate embodiments 46-60, whereinthe polymer matrix comprises up to about 20% of the hydrophiliccomponent.62. The apparatus of the combined or separate embodiments 46-61, whereinthe polymer matrix comprises up to about 10% of the hydrophiliccomponent.63. The apparatus of the combined or separate embodiments 46-62, whereinan initial release rate of the therapeutic agent from the polymer matrixis between about 0.05-10%/minute.64. The apparatus of the combined or separate embodiments 46-63, whereinan initial release rate of the therapeutic agent from the polymer matrixis between about 0.5-10%/minute.65. The apparatus of the combined or separate embodiments 46-64, whereinan initial release rate of the therapeutic agent from the polymer matrixis between about 1-10%/minute.66. The apparatus of the combined or separate embodiments 46-65, whereinan initial release rate of the therapeutic agent from the polymer matrixis between about 2-10%/minute.67. The apparatus of the combined or separate embodiments 46-66, whereinthe hydrophilic component is PEG-PLGA.68. The apparatus of the combined or separate embodiments 46-67, whereinthe biodegradable polymer is a hydrophobic polymer selected from PLA,α-hydroxy acids, polycaprolactones, polyanhydrides, and co-polymersthereof.69. The apparatus of the combined or separate embodiments 46-68, whereinthe α-hydroxy acid is PLGA.70. The apparatus of the combined or separate embodiments 46-69, whereinthe microstructures are detachable from the substrate.71. The apparatus of the combined or separate embodiments 46-70, whereinthe therapeutic agent is selected from a drug, a small molecule, apeptide or protein, or a vaccine.72. A microstructure apparatus, comprising:

an approximately planar substrate having a first surface and a secondsurface opposed thereto;

a microstructure array comprising a plurality of microstructurescontacting the first surface of the substrate and fixedly attachedthereto, the microstructures being formed of a polymer matrix comprisingat least one polymer and at least one therapeutic agent;

wherein a ratio of therapeutic agent to polymer in the matrix is low;

wherein an initial release rate of the therapeutic agent from thepolymer matrix is between about 0.05-10%/minute;

wherein release of the therapeutic agent from the polymer matrix issustained for a period of at least about 1-144 hours.

73. The apparatus of embodiment 72, wherein the ratio of therapeuticagent to polymer is between about 1:2 to 1:25.74. The apparatus of the combined or separate embodiments 72-73, whereinthe ratio of therapeutic agent to polymer is between about 1:2 to 1:20.75. The apparatus of the combined or separate embodiments 72-74, whereinthe ratio of therapeutic agent to polymer is between about 1:2 to 1:15.76. The apparatus of the combined or separate embodiments 72-75, whereinthe ratio of therapeutic agent to polymer is between about 1:2 to 1:10.77. The apparatus of the combined or separate embodiments 72-76, whereinthe ratio of therapeutic agent to polymer is between about 1:2 to 1:4.78. The apparatus of the combined or separate embodiments 72-77, whereinthe polymer matrix comprises at least one water insoluble, biodegradablepolymer.79. The apparatus of any the combined or separate embodiments 72-78,wherein the water insoluble, biodegradable polymer is selected frompolylactide, polyglycolide, and co-polymers thereof.80. The apparatus of the combined or separate embodiments 72-79, whereinthe initial release rate is between about 0.5%/minute.81. The apparatus of the combined or separate embodiments 72-80, whereinthe initial release rate of the therapeutic agent from the polymermatrix is less than 10%/minute.82. The apparatus of the combined or separate embodiments 72-81, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 144 hours.83. The apparatus of the combined or separate embodiments 72-82, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 72 hours.84. The apparatus of the combined or separate embodiments 72-83, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 24 hours.85. The apparatus of the combined or separate embodiments 72-84, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 12 hours.86. The apparatus of the combined or separate embodiments 72-85, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 6 hours.87. The apparatus of the combined or separate embodiments 72-86, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 3 hours.88. The apparatus of the combined or separate embodiments 72-87, whereinrelease of the therapeutic agent from the polymer matrix is sustainedfor a period of at least about 1 hour.89. The apparatus of the combined or separate embodiments 72-88, whereinthe therapeutic agent is selected from a drug, a small molecule, apeptide or protein, or a vaccine.90. The apparatus of the combined or separate embodiments 72-89, whereinthe microstructures are detachable from the substrate.91. A method of making a sustained release microstructure apparatus,comprising:

dissolving or suspending a therapeutic agent in a solvent to form atherapeutic agent solution or suspension;

dissolving at least one water insoluble, biodegradable polymer in asolvent to form a polymer solution;

mixing the therapeutic agent solution or suspension and the polymersolution or suspension to form a polymer matrix solution or suspension;

dispensing the polymer matrix solution or suspension on a mold having anarray of microstructure cavities;

filling the microstructure cavities in the mold;

removing excess solution or suspension polymer matrix on the moldsurface; and drying the matrix to form a plurality of microstructures;

dispensing a basement or backing layer on the mold surface;

drying the basement or backing layer.

92. The method of embodiment 91, further comprising:

affixing the basement or backing layer to a substrate.

93. The method of the combined or separate embodiments 91-92, furthercomprising:

using a nonwoven or porous film double coated with adhesive to affix thebasement or backing layer to a substrate.

94. The method of the combined or separate embodiments 91-93, wherein atleast one of the solvents is selected from DMSO and acetonitrile.95. The method of the combined or separate embodiments 91-94, whereinfilling the microstructure cavities comprises pressurizing the mold.96. The method of the combined or separate embodiments 91-95, whereinthe therapeutic agent is crystalline, further comprising:

heating the plurality of microstructures to about 110° C. for about 1hour; and storing the microstructures in a dry cabinet for about 10days.

97. The method of the combined or separate embodiments 91-96, whereinthe heating is performed in a convection oven.98. A method of modulating an initial release rate of a therapeuticagent from a microstructure apparatus comprising a plurality ofmicrostructures formed of a polymer matrix comprising at least onepolymer and at least one therapeutic agent, the method comprising:

(a) wherein the at least one polymer comprises at least one highmolecular weight polymer and at least one low molecular weight polymer,adjusting a ratio of the high molecular weight polymers to low molecularweight polymers in the polymer matrix to achieve a desired initialrelease rate of therapeutic agent from the polymer matrix;

(b) adjusting a ratio of therapeutic agent to polymer in the polymermatrix;

(c) adding at least one hydrophilic component to the polymer matrix;and/or

(d) selecting a solvent for preparing the polymer matrix that provides adesired initial release rate.

99. The method of embodiment 98, wherein (a) comprises increasing theratio of high molecular weight polymer in the matrix to increase theinitial release rate.100. The method of the combined or separate embodiments 98-99, wherein(a) comprises increasing the ratio of low molecular weight polymer inthe matrix to decrease the initial release rate.101. The method of the combined or separate embodiments 98-100, wherein(b) comprises increasing the ratio of therapeutic agent in the matrix toincrease the initial release rate.102. The method of the combined or separate embodiments 98-101, wherein(b) comprises decreasing the ratio of low molecular weight polymer inthe matrix to decrease the initial release rate.103. The method of the combined or separate embodiments 98-102, wherein(c) comprises adding the hydrophilic component as about 10-40% of thematrix to increase the initial release rate.104. The method of the combined or separate embodiments 98-103, whereinthe hydrophilic component is PEG-PLGA.105. The method of the combined or separate embodiments 98-104, whereinthe at least one polymer is a water insoluble, biodegradable polymer.106. The method of the combined or separate embodiments 98-105, whereinthe water insoluble, biodegradable polymer is selected from polylactide,polyglycolide, and co-polymers thereof.107. The method of the combined or separate embodiments 98-106, wherein(d) comprises choosing one of DMSO or acetonitrile as the solvent.108. The method of the combined or separate embodiments 98-107, wherein(d) comprises choosing DMSO as the solvent to lower the initial releaserate.109. The method of the combined or separate embodiments 98-108, wherein(d) comprises choosing acetonitrile as the solvent to increase theinitial release rate.110. A microstructure apparatus, comprising:

an approximately planar substrate having a first surface and a secondsurface opposed thereto; and

a microstructure array comprising a plurality of microstructurescontacting the first surface of the substrate and fixedly attachedthereto;

wherein at least a portion of the microstructures has a distal portiondimensioned to penetrate a stratum corneum layer of a subject's skin,and a proximal portion that is dimensioned so that it does not penetratethe skin;

wherein the distal portion and proximal portion are each formed of apolymer matrix comprising (i) a biodegradable polymer, and (ii) at leastone therapeutic agent.

111. The microstructure apparatus of embodiment 110, further comprising:

a backing layer positioned between the proximal portion and thesubstrate, the backing layer being formed of a polymer matrix comprising(i) a biodegradable polymer, and (ii) the at least one therapeuticagent.

112. The apparatus of the combined or separate embodiments 110-111,wherein the biodegradable polymer is a water soluble biodegradablepolymer.113. The apparatus of the combined or separate embodiments 110-112,wherein the biodegradable polymer is a water insoluble biodegradablepolymer.114. The apparatus of the combined or separate embodiments 110-113,wherein the therapeutic agent is selected from a drug, a small molecule,a peptide or protein, or a vaccine.115. The apparatus of the combined or separate embodiments 110-114,wherein release of the therapeutic agent from the polymer matrix issustained for a period of at least about 0.1-24 hours.116. The apparatus of the combined or separate embodiments 110-115,wherein release of the therapeutic agent from the polymer matrix issustained for a period of at least about 0.5-10 hours.117. The apparatus of any the combined or separate embodiments 110-116,wherein release of the therapeutic agent from the polymer matrix issustained for a period of at least about 0.5-4 hours.118. The apparatus of the combined or separate embodiments 110-117,wherein release of the therapeutic agent from the polymer matrix issustained for a period of at least about 0.5-4 hours.119. The apparatus of the combined or separate embodiments 110-118,wherein release of the therapeutic agent from the polymer matrix issustained for a period of at least about 0.1-1 hours.120. The apparatus of the combined or separate embodiments 110-119,where the microstructure array is suitable to be worn for at least 1-24hours.121. A microstructure apparatus, comprising:

a substrate having a first surface and a second surface opposed thereto;

a plurality of microstructures extending outwardly from the firstsurface of the substrate;

at least a portion of the microstructures comprising at least onetherapeutic agent; and

an adhesive coating applied to at least one of a) at least a portion ofat least some of the plurality of microstructures, or b) at least aportion of the substrate first surface between the microstructures.

122. The microstructure apparatus of embodiment 121, wherein at least aportion of the microstructures comprise a biodegradable distal layer andat least one non-biodegradable proximal layer positioned between thedistal layer and the first surface of the substrate.123. The microstructure apparatus of the combined or separateembodiments 121-122, wherein at least a portion of the microstructuresare biodegradable.124. The microstructure apparatus of the combined or separateembodiments 121-123, wherein the therapeutic agent is a drug, asmall-molecule agent, a protein or peptide, or a vaccine.125. The microstructure apparatus of the combined or separateembodiments 121-124, wherein the adhesive coating comprises an adhesiveselected from a medical adhesive, a tissue adhesive, or a surgicaladhesive.126. The microstructure apparatus of the combined or separateembodiments 121-125, wherein the medical adhesive is selected fromacrylic adhesives, silicone based adhesives, hydrogel adhesives, andsynthetic elastomer adhesives.127. The microstructure apparatus of the combined or separateembodiments 121-126, wherein the tissue adhesive is a cyanoacrylatepolymer.128. The microstructure apparatus of the combined or separateembodiments 121-127, wherein the cyanoacrylate polymer is selected fromn-butyl-2-cyanoacrylate, and isobutyl cyanoacrylate.129. The microstructure apparatus of the combined or separateembodiments 121-128, wherein the adhesive coating comprises a fibrinadhesive.130. The microstructure apparatus of the combined or separateembodiments 121-129, wherein the adhesive coating comprises a bioactivefilm.131. The microstructure apparatus of the combined or separateembodiments 121-130, wherein the adhesive coating comprises a pressuresensitive adhesive.132. The microstructure apparatus of the combined or separateembodiments 121-131, wherein the pressure sensitive adhesive is anacrylic pressure sensitive adhesive.133. The microstructure apparatus of the combined or separateembodiments 121-132, wherein the adhesive coating comprises arubber-based adhesive.134. The microstructure apparatus of the combined or separateembodiments 121-133, wherein the adhesive coating is biodegradable.135. The microstructure apparatus of the combined or separateembodiments 121-134, wherein the adhesive coating is non-continuous.136. The microstructure apparatus of the combined or separateembodiments 121-135, wherein the adhesive coating includes a pluralityof holes.137. The microstructure apparatus of the combined or separateembodiments 121-136, wherein the adhesive coating is porous.138. The microstructure apparatus of the combined or separateembodiments 121-137, wherein the adhesive coating has a reduced adhesionover time.139. The microstructure apparatus of the combined or separateembodiments 121-138, wherein the adhesive coating is applied to at leastabout 10-100% of the microstructures in the array.140. The microstructure apparatus of the combined or separateembodiments 121-139, wherein about 10-95% of each coated microstructurehas an adhesive coating.141. The microstructure apparatus of the combined or separateembodiments 121-140, wherein the adhesive coating is applied to a distalportion of the microstructures.142. The microstructure apparatus of the combined or separateembodiments 121-141, wherein the adhesive coating is applied to aproximal portion of the microstructures.143. A microstructure apparatus, comprising:

a substrate having a first surface and a second surface opposed thereto;

a plurality of microstructures extending outwardly from the firstsurface of the substrate;

a plurality of openings extending through the substrate and positionedbetween at least some of the plurality of microstructures; and

an adhesive coating applied to at least a portion of the substratesecond surface such that the adhesive is capable of contacting asubject's skin through the openings when placed on the skin.

144. The microstructure apparatus of embodiment 143, wherein theadhesive coating is applied to all or substantially all of the substratesecond surface.145. The microstructure apparatus of the combined or separateembodiments 143-144, wherein the adhesive coating is applied thesubstrate second surface in the region of the openings.146. The microstructure apparatus of the combined or separateembodiments 143-145, further comprising a backing layer positioned overthe adhesive coating.147. The microstructure apparatus of the combined or separateembodiments 143-146, wherein at least a portion of the microstructuresare at least partially biodegradable.148. The microstructure apparatus of the combined or separateembodiments 143-147, wherein the therapeutic agent is a drug, asmall-molecule agent, a protein or peptide, or a vaccine.149. The microstructure apparatus of the combined or separateembodiments 143-148, wherein the adhesive coating comprises an adhesiveselected from a medical adhesive, a tissue adhesive, or a surgicaladhesive.150. The microstructure apparatus of the combined or separateembodiments 143-149, wherein the medical adhesive is selected fromacrylic adhesives, silicone based adhesives, hydrogel adhesives, andsynthetic elastomer adhesives.151. The microstructure apparatus of the combined or separateembodiments 143-150, wherein the tissue adhesive is a cyanoacrylatepolymer.152. The microstructure apparatus of the combined or separateembodiments 143-151, wherein the cyanoacrylate polymer is selected fromn-butyl-2-cyanoacrylate, and isobutyl cyanoacrylate.153. The microstructure apparatus of the combined or separateembodiments 143-152, wherein the adhesive coating comprises a fibrinadhesive.154. The microstructure apparatus of the combined or separateembodiments 143-153, wherein the adhesive coating comprises a bioactivefilm.155. The microstructure apparatus of the combined or separateembodiments 143-154, wherein the adhesive coating comprises a pressuresensitive adhesive.156. The microstructure apparatus of the combined or separateembodiments 143-155, wherein the pressure sensitive adhesive is anacrylic pressure sensitive adhesive.157. The microstructure apparatus of the combined or separateembodiments 143-156, wherein the adhesive coating comprises arubber-based adhesive.158. The microstructure apparatus of the combined or separateembodiments 143-157, wherein the adhesive coating is biodegradable.159. The microstructure apparatus of the combined or separateembodiments 143-158, wherein the adhesive coating is non-continuous.160. The microstructure apparatus of the combined or separateembodiments 143-159, wherein the adhesive coating includes a pluralityof holes.161. The microstructure apparatus of the combined or separateembodiments 143-160, wherein the adhesive coating is porous.162. The microstructure apparatus of the combined or separateembodiments 143-161, wherein the adhesive coating has a reduced adhesionover time.163. The microstructure apparatus of the combined or separateembodiments 143-162, wherein the adhesive coating is applied to at leastabout 10-100% of the microstructures in the array.164. The microstructure apparatus of the combined or separateembodiments 143-163, wherein about 10-95% of each coated microstructurehas an adhesive coating.165. The microstructure apparatus of the combined or separateembodiments 143-164, wherein the adhesive coating is applied to a distalportion of the microstructures.166. The microstructure apparatus of the combined or separateembodiments 143-165, wherein the adhesive coating is applied to aproximal portion of the microstructures.167. A system comprising:

the microstructure apparatus of the combined or separate embodiments1-166; and

an applicator for applying the microstructure apparatus to a patient'sskin.

168. A method of delivering a therapeutic agent to a subject for anextended period of time, comprising:

applying a microstructure apparatus of any previous claim to a skin siteof the subject;

adhering the microstructure apparatus to the skin;

delivering the therapeutic agent from the microstructure array to thesubject; and

removing the microstructure apparatus after at least about 10 minutes.

169. The method of embodiment 168, wherein the microstructure apparatusis removed after at least about 15 minutes.170. The method of the combined or separate embodiments 168-169, whereinthe microstructure apparatus is removed after at least about 20 minutes.171. The method of the combined or separate embodiments 168-170, whereinthe microstructure apparatus is removed after at least about 30 minutes.172. The method of the combined or separate embodiments 168-171, whereinthe microstructure apparatus is removed after at least about 45 minutes.173. The method of the combined or separate embodiments 168-172, whereinthe microstructure apparatus is removed after at least about 1 hour.174. The method of the combined or separate embodiments 168-173, whereinthe microstructure apparatus is removed after at least about 1-24 hours.175. The method of the combined or separate embodiments 168-174, whereinthe microstructure apparatus is removed after at least about 1-5 days.176. The method of the combined or separate embodiments 168-175, whereinat least about 10-100% of a total dose of the therapeutic agent isdelivered to the subject.177. The method of the combined or separate embodiments 168-176, whereinat least about 50-100% of a total dose of the therapeutic agent isdelivered to the subject.178. The method of the combined or separate embodiments 168-177, whereinat least about 60-100% of a total dose of the therapeutic agent isdelivered to the subject.179. The method of the combined or separate embodiments 168-178, whereinat least about 70-100% of a total dose of the therapeutic agent isdelivered to the subject.180. The method of the combined or separate embodiments 168-179, whereinat least about 75-100% of a total dose of the therapeutic agent isdelivered to the subject.181. The method of the combined or separate embodiments 168-180, whereinat least about 80-100% of a total dose of the therapeutic agent isdelivered to the subject.182. The method of the combined or separate embodiments 168-181, whereinat least about 90-100% of a total dose of the therapeutic agent isdelivered to the subject.183. The method of the combined or separate embodiments 168-182, whereinat least about 95-100% of a total dose of the therapeutic agent isdelivered to the subject.

184. The method of the combined or separate embodiments 168-183, furthercomprising:

prior to applying the microstructure apparatus, positioning themicrostructure apparatus on a plunger of an applicator;

actuating the applicator to release the plunger;

impacting the skin with the microstructure apparatus;

removing the applicator with the microstructure apparatus remaining onthe skin site for an extended period of time.

185. The method of the combined or separate embodiments 168-184, furthercomprising:

pressing the microstructure apparatus against the skin site to push theadhesive through the openings and into contact with the skin site.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced are interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

All patents, patent applications, and publications mentioned herein arehereby incorporated by reference in their entireties. However, where apatent, patent application, or publication containing expressdefinitions is incorporated by reference, those express definitionsshould be understood to apply to the incorporated patent, patentapplication, or publication in which they are found, and not necessarilyto the text of this application, in particular the claims of thisapplication, in which instance, the definitions provided herein aremeant to supersede.

What is claimed is:
 1. A microstructure apparatus, comprising: anapproximately planar substrate having a first surface and a secondsurface opposed thereto; and a microstructure array comprising aplurality of microstructures contacting the first surface of thesubstrate and fixedly attached thereto, the microstructures being formedof a polymer matrix comprising at least one of: (a) a water insoluble,biodegradable polymer, and at least one therapeutic agent; (b) at leastone low molecular weight polymer, at least one high molecular weightpolymer, and at least one therapeutic agent; (c) at least onebiodegradable polymer, a hydrophilic component, and at least onetherapeutic agent; or (d) at least one polymer and at least onetherapeutic agent, wherein a ratio of therapeutic agent to polymer inthe matrix is low; and wherein release of the therapeutic agent from thepolymer matrix is sustained for a period of at least about 1-144 hours.2. The microstructure apparatus of claim 1, wherein the water insolublepolymer of (a) is selected from polylactide, polyglycolide, andco-polymers thereof.
 3. The microstructure apparatus of claim 1, whereinthe polymer matrix of (a) comprises at least one of: i) about 1-50%therapeutic agent; and ii) about 50-99% of the water insoluble,biodegradable polymer.
 4. The microstructure apparatus of claim 1,wherein an initial release rate of the therapeutic agent from thepolymer matrix is between about 0.05-10%/minute.
 5. The microstructureapparatus of claim 1, wherein at least a portion of the microstructuresare detachable from the substrate.
 6. The microstructure apparatus ofclaim 1, wherein the therapeutic agent is selected from a drug, a smallmolecule, a peptide or protein, or a vaccine.
 7. The microstructureapparatus of claim 1, wherein the low molecular weight polymer of (b)has a molecular weight of between about 1-10K Da.
 8. The microstructureapparatus of claim 1, wherein the high molecular weight polymer of (b)has a molecular weight of between about 50-300K Da.
 9. Themicrostructure apparatus of claim 1, wherein the low molecular weightpolymer and high molecular weight polymers of (b) are present in a ratioof about 1:1-1:10.
 10. The microstructure apparatus of claim 1, whereinthe polymer matrix of (c) comprises about 5%-40% of the hydrophiliccomponent.
 11. The microstructure apparatus of claim 1, wherein thehydrophilic component of (c) is PEG-PLGA.
 12. The microstructureapparatus of claim 1, wherein the biodegradable polymer of (c) is ahydrophobic polymer selected from PLA, α-hydroxy acids,polycaprolactones, polyanhydrides, and co-polymers thereof.
 13. Themicrostructure apparatus of claim 12, wherein the α-hydroxy acid isPLGA.
 14. The microstructure apparatus of claim 1, wherein the ratio oftherapeutic agent to polymer of (d) is between about 1:2 to 1:25. 15.The microstructure apparatus of claim 1, further comprising: a backinglayer positioned between a proximal portion of the plurality ofmicrostructures and the substrate, the backing layer being formed of asecond polymer matrix comprising (i) a biodegradable polymer, and (ii)the at least one therapeutic agent.
 16. The microstructure apparatus ofclaim 1, further comprising: an adhesive coating applied to at least oneof 0 at least a portion of at least some of the plurality ofmicrostructures, ii) at least a portion of the substrate first surfacebetween the microstructures, or iii) the apparatus further including aplurality of openings extending through the substrate and positionedbetween at least some of the plurality of microstructures, the adhesivecoating being applied to at least a portion of the substrate secondsurface such that the adhesive is capable of contacting a subject's skinthrough the openings when placed on the skin.
 17. The microstructureapparatus of claim 16, wherein the adhesive coating comprises anadhesive selected from a medical adhesive, a tissue adhesive, a surgicaladhesive, a fibrin adhesive, a bioactive film, a pressure sensitiveadhesive, or a rubber-based adhesive.
 18. The microstructure apparatusof claim 17, wherein the medical adhesive is selected from acrylicadhesives, silicone based adhesives, hydrogel adhesives, and syntheticelastomer adhesives.
 19. The microstructure apparatus of claim 17,wherein the tissue adhesive is a cyanoacrylate polymer.
 20. Themicrostructure apparatus of claim 19, wherein the cyanoacrylate polymeris selected from n-butyl-2-cyanoacrylate, and isobutyl cyanoacrylate.21. The microstructure apparatus of claim 16, wherein the adhesivecoating is non-continuous.
 22. A method of making a sustained releasemicrostructure apparatus, comprising: dissolving or suspending atherapeutic agent in a solvent to form a therapeutic agent solution orsuspension; dissolving at least one water insoluble, biodegradablepolymer in a solvent to form a polymer solution; mixing the therapeuticagent solution or suspension and the polymer solution or suspension toform a polymer matrix solution or suspension; dispensing the polymermatrix solution or suspension on a mold having an array ofmicrostructure cavities; filling the microstructure cavities in themold; removing excess solution or suspension polymer matrix on the moldsurface; and drying the matrix to form a plurality of microstructures;dispensing a basement or backing layer on the mold surface; drying thebasement or backing layer.
 23. The method of claim 22, furthercomprising: affixing the basement or backing layer to a substrate. 24.The method of claim 22, wherein at least one of the solvents is selectedfrom DMSO and acetonitrile.
 25. The method of claim 22, wherein fillingthe microstructure cavities further comprises pressurizing the mold. 26.The method of claim 22, wherein the therapeutic agent is crystalline,further comprising: heating the plurality of microstructures to about110° C. for about 1 hour; and storing the microstructures in a drycabinet for about 10 days.
 27. A method of modulating an initial releaserate of a therapeutic agent from a microstructure apparatus comprising aplurality of microstructures formed of a polymer matrix comprising atleast one polymer and at least one therapeutic agent, the methodcomprising at least one of: (a) wherein the at least one polymercomprises at least one high molecular weight polymer and at least onelow molecular weight polymer, adjusting a ratio of the high molecularweight polymers to low molecular weight polymers in the polymer matrixto achieve a desired initial release rate of therapeutic agent from thepolymer matrix; (b) adjusting a ratio of therapeutic agent to the atleast one polymer in the polymer matrix; (c) adding at least onehydrophilic component to the polymer matrix; and/or (d) selecting asolvent for preparing the polymer matrix that provides a desired initialrelease rate.
 28. The method of claim 27, wherein (a) comprises one of:i) increasing the ratio of high molecular weight polymer in the matrixto increase the initial release rate, or ii) increasing the ratio of lowmolecular weight polymer in the matrix to decrease the initial releaserate.
 29. The method of claim 27, wherein (b) comprises one of: i)increasing the ratio of therapeutic agent in the matrix to increase theinitial release rate, or ii) decreasing the ratio of low molecularweight polymer in the matrix to decrease the initial release rate. 30.The method of claim 27, wherein (c) comprises adding the hydrophiliccomponent as about 10-40% of the matrix to increase the initial releaserate.
 31. The method of claim 27, wherein (d) comprises: i) selectingDMSO as the solvent to lower the initial release rate; or ii) selectingacetonitrile as the solvent to increase the initial release rate.
 32. Amethod of delivering a therapeutic agent to a subject for an extendedperiod of time, comprising: applying the microstructure apparatus ofclaim 1 to a skin site of the subject; adhering the microstructureapparatus to the skin; delivering the therapeutic agent from themicrostructure array to the subject; and removing the microstructureapparatus after at least about 10 minutes.
 33. The method of claim 32,wherein the microstructure apparatus is removed after at least about 15minutes to 5 days.
 34. The method of claim 32, comprising delivering atleast about 10-100% of a total dose of the therapeutic agent to thesubject.
 35. The method of claim 32, further comprising: whereinapplying the microstructure apparatus comprises: positioning themicrostructure apparatus on a plunger of an applicator; actuating theapplicator to release the plunger; impacting the skin with themicrostructure apparatus; removing the applicator with themicrostructure apparatus remaining on the skin site for an extendedperiod of time.